dna mutations essay

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What are mutation hotspots?

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• Verywell Health - What Is a Mutation?
• North Dakota State University - Genes and Mutations
• Cleveland Clinic - Genetic Mutations in Humans
• Live Science - What are Mutations?
• University of California, Berkeley - Understanding Evolution - The causes of mutations
• National Center for Biotechnology Information - PubMed Central - Muons, mutations, and planetary shielding
• Learn Genetics - What is Mutation?
• Biology LibreTexts - Mutations
• Nature - Genetic Mutation
• Academia - Mutation
• Khan Academy - An introduction to genetic mutations
• Iowa State University Digital Press - DNA Mutations
• mutation - Children's Encyclopedia (Ages 8-11)

How are mutations passed to offspring?

An individual offspring inherits mutations only when mutations are present in parental egg or sperm cells (germinal mutations). All of the offspring’s cells will carry the mutated DNA , which often confers some serious malfunction, as in the case of a human genetic disease such as  cystic fibrosis .

Why does mutation occur?

Mutations in DNA occur for different reasons. For example, environmental factors, such as exposure to ultraviolet radiation or certain chemicals, can induce changes in the DNA sequence. Mutations can also occur because of hereditary factors.

Mutation hotspots (or mutational hotspots) are segments of DNA that are especially prone to genetic alteration. The increased susceptibility of these areas of DNA to mutation is attributed to interactions between mutation-inducing factors, the structure and function of the DNA sequence, and enzymes involved in DNA repair, replication, and modification.

mutation , an alteration in the genetic material (the genome ) of a cell of a living organism or of a virus that is more or less permanent and that can be transmitted to the cell’s or the virus’s descendants. (The genomes of organisms are all composed of DNA , whereas viral genomes can be of DNA or RNA ; see heredity: The physical basis of heredity .) Mutation in the DNA of a body cell of a multicellular organism ( somatic mutation ) may be transmitted to descendant cells by DNA replication and hence result in a sector or patch of cells having abnormal function, an example being cancer . Mutations in egg or sperm cells ( germinal mutations ) may result in an individual offspring all of whose cells carry the mutation, which often confers some serious malfunction, as in the case of a human genetic disease such as cystic fibrosis . Mutations result either from accidents during the normal chemical transactions of DNA, often during replication, or from exposure to high-energy electromagnetic radiation (e.g., ultraviolet light or X-rays) or particle radiation or to highly reactive chemicals in the environment . Because mutations are random changes, they are expected to be mostly deleterious , but some may be beneficial in certain environments . In general, mutation is the main source of genetic variation , which is the raw material for evolution by natural selection .

The genome is composed of one to several long molecules of DNA, and mutation can occur potentially anywhere on these molecules at any time. The most serious changes take place in the functional units of DNA, the genes . A mutated form of a gene is called a mutant allele . A gene is typically composed of a regulatory region, which is responsible for turning the gene’s transcription on and off at the appropriate times during development, and a coding region, which carries the genetic code for the structure of a functional molecule, generally a protein . A protein is a chain of usually several hundred amino acids . Cells make 20 common amino acids, and it is the unique number and sequence of these that give a protein its specific function. Each amino acid is encoded by a unique sequence, or codon , of three of the four possible base pairs in the DNA (A–T, T–A, G–C, and C–G, the individual letters referring to the four nitrogenous bases adenine , thymine , guanine , and cytosine ). Hence, a mutation that changes DNA sequence can change amino acid sequence and in this way potentially reduce or inactivate a protein’s function. A change in the DNA sequence of a gene’s regulatory region can adversely affect the timing and availability of the gene’s protein and also lead to serious cellular malfunction. On the other hand, many mutations are silent, showing no obvious effect at the functional level. Some silent mutations are in the DNA between genes, or they are of a type that results in no significant amino acid changes.

Mutations are of several types. Changes within genes are called point mutations . The simplest kinds are changes to single base pairs, called base-pair substitutions. Many of these substitute an incorrect amino acid in the corresponding position in the encoded protein, and of these a large proportion result in altered protein function. Some base-pair substitutions produce a stop codon. Normally, when a stop codon occurs at the end of a gene, it stops protein synthesis , but, when it occurs in an abnormal position, it can result in a truncated and nonfunctional protein. Another type of simple change, the deletion or insertion of single base pairs, generally has a profound effect on the protein because the protein’s synthesis, which is carried out by the reading of triplet codons in a linear fashion from one end of the gene to the other, is thrown off. This change leads to a frameshift in reading the gene such that all amino acids are incorrect from the mutation onward. More-complex combinations of base substitutions , insertions, and deletions can also be observed in some mutant genes.

Mutations that span more than one gene are called chromosomal mutations because they affect the structure, function, and inheritance of whole DNA molecules (microscopically visible in a coiled state as chromosomes ). Often these chromosome mutations result from one or more coincident breaks in the DNA molecules of the genome (possibly from exposure to energetic radiation), followed in some cases by faulty rejoining. Some outcomes are large-scale deletions, duplications, inversions, and translocations. In a diploid species (a species, such as human beings, that has a double set of chromosomes in the nucleus of each cell), deletions and duplications alter gene balance and often result in abnormality. Inversions and translocations involve no loss or gain and are functionally normal unless a break occurs within a gene. However, at meiosis (the specialized nuclear divisions that take place during the production of gametes —i.e., eggs and sperm), faulty pairing of an inverted or translocated chromosome set with a normal set can result in gametes and hence progeny with duplications and deletions.

Loss or gain of whole chromosomes results in a condition called aneuploidy . One familiar result of aneuploidy is Down syndrome , a chromosomal disorder in which humans are born with an extra chromosome 21 (and hence bear three copies of that chromosome instead of the usual two). Another type of chromosome mutation is the gain or loss of whole chromosome sets. Gain of sets results in polyploidy —that is, the presence of three, four, or more chromosome sets instead of the usual two. Polyploidy has been a significant force in the evolution of new species of plants and animals. ( See also evolution: Polyploidy .)

Most genomes contain mobile DNA elements that move from one location to another. The movement of these elements can cause mutation, either because the element arrives in some crucial location, such as within a gene, or because it promotes large-scale chromosome mutations via recombination between pairs of mobile elements in different locations.

At the level of whole populations of organisms, mutation can be viewed as a constantly dripping faucet introducing mutant alleles into the population, a concept described as mutational pressure. The rate of mutation differs for different genes and organisms. In RNA viruses, such as the human immunodeficiency virus (HIV; see AIDS ), replication of the genome takes place within the host cell using a mechanism that is prone to error. Hence, mutation rates in such viruses are high. In general, however, the fate of individual mutant alleles is never certain. Most are eliminated by chance. In some cases a mutant allele can increase in frequency by chance, and then individuals expressing the allele can be subject to selection, either positive or negative. Hence, for any one gene the frequency of a mutant allele in a population is determined by a combination of mutational pressure, selection, and chance.

ENCYCLOPEDIC ENTRY

A mutation is a change in the sequence of genetic letters, called bases, within a molecule of DNA.

Biology, Genetics

York Grown Strawberries

Mutations occur throughout the natural world, and fuel the process of natural selection. In cultivated crops like strawberries, farmers may help this process along by selectively growing plants with mutations that make the fruits more resilient against di

Photograph by Jim Richardson

A mutation is a change in the structure of a gene , the unit of heredity. Genes are made of deoxyribonucleic acid ( DNA ), a long molecule composed of building blocks called nucleotides . Each nucleotide is built around one of four different subunits called bases. These bases are known as guanine, cytosine, adenine, and thymine. A gene carries information in the sequence of its nucleotides , just as a sentence carries information in the sequence of its letters.

One type of mutation is a change in a base. This is called a point mutation and it is like changing one letter in a word. Most genes carry instructions for making proteins . When a base is changed in a gene , different results are possible, depending on which base is changed and what it is changed into. The gene may produce an altered protein , it may produce no protein , or it may produce the usual protein . Most mutations are not harmful, but some can be. A harmful mutation can result in a genetic disorder or even cancer.

Another kind of mutation is a chromosomal mutation . Chromosomes , located in the cell nucleus, are tiny threadlike structures that carry genes . A chromosome consists of a molecule of DNA together with proteins . Sometimes, a long segment of DNA is inserted into a chromosome , deleted from a chromosome , flipped around within a chromosome , duplicated, or moved from one chromosome to another. Such changes are usually very harmful.

One example of a chromosomal mutation is a condition called Down syndrome. In each cell, humans normally have forty-six chromosomes, consisting of two copies of the twenty-three kinds of chromosomes. Down syndrome usually results from the presence of one extra copy of a particular chromosome, or an extra portion of that chromosome. The presence of that extra chromosome leads to problems with certain organs of the body, such as the heart. It can also lead to leukemia—a cancer of the blood-forming cells—and produce mental disabilities. Many people with Down syndrome also have distinct facial features.

Mutations can be inherited or acquired during a person's lifetime. Mutations that an individual inherits from their parents are called hereditary mutations . They are present in all body cells and can be passed down to new generations . Acquired mutations occur during an individual’s life. If an acquired mutation occurs in an egg or sperm cell, it can be passed down to the individual’s offspring. Once an acquired mutation is passed down, it is a hereditary mutation . Acquired mutations are not passed down if they occur in the somatic cells, meaning body cells other than sperm cells and egg cells. Some acquired mutations occur spontaneously and randomly in genes . Other mutations are caused by environmental factors, such as exposure to certain chemicals or radiation.

Mutations occur throughout the natural world. Some mutations are beneficial and increase the possibility that an organism will thrive and pass on its genes to the next generation. When mutations improve survival or reproduction, the process of natural selection will cause the mutation to become more common over time. When mutations are harmful, they become less common over time. Therefore, mutation is a force that helps drive evolution.

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Open Access

What is mutation? A chapter in the series: How microbes “jeopardize” the modern synthesis

Affiliations Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America, The Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America

* E-mail: [email protected]

• Devon M. Fitzgerald, 
• Susan M. Rosenberg

Published: April 1, 2019

• https://doi.org/10.1371/journal.pgen.1007995
• Reader Comments

Mutations drive evolution and were assumed to occur by chance: constantly, gradually, roughly uniformly in genomes, and without regard to environmental inputs, but this view is being revised by discoveries of molecular mechanisms of mutation in bacteria, now translated across the tree of life. These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation. Mutation is also nonrandom in genomic space, with multiple simultaneous mutations falling in local clusters, which may allow concerted evolution—the multiple changes needed to adapt protein functions and protein machines encoded by linked genes. Molecular mechanisms of stress-inducible mutation change ideas about evolution and suggest different ways to model and address cancer development, infectious disease, and evolution generally.

Citation: Fitzgerald DM, Rosenberg SM (2019) What is mutation? A chapter in the series: How microbes “jeopardize” the modern synthesis. PLoS Genet 15(4): e1007995. https://doi.org/10.1371/journal.pgen.1007995

Editor: W. Ford Doolittle, Dalhousie University, CANADA

Copyright: © 2019 Fitzgerald, Rosenberg. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the American Cancer Society Postdoctoral Fellowship 132206-PF-18-035-01-DMC (DMF) and NIH grant R35-GM122598. The funders had no role in the preparation of the article.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Mutation is any change in the sequence of an organism’s genome or the process by which the changes occur. Mutations range from single-basepair alterations to megabasepair deletions, insertions, duplications, and inversions. Though seemingly simple, ideas about mutation became entangled with the initially simplifying assumptions of both Darwin himself and the “Modern Synthesis”—the geneticists who embraced Darwin in the pre-DNA early 20th century, beginning evolutionary biology. The assumptions of purely “chance” mutations that occur constantly, gradually, and uniformly in genomes have underpinned biology for almost a century but began as a “wait-and-see”–based acknowledgment by early evolutionary biologists that they did not know the chemical nature of genes or how mutations in genes might occur.

Darwin considered generation of variation by chance to be a simplifying assumption, given that the origins of variation (and genes!) were unknown in his time, but he appears to have thought chance variation to be unlikely: “I have hitherto sometimes spoken as if the variations—so common and multiform in organic beings under domestication, and in a lesser degree in those in a state of nature—had been due to chance. This, of course, is a wholly incorrect expression, but it serves to acknowledge plainly our ignorance of the cause of particular variation [Chapter 5, 1].”

He also described multiple instances in which the degree and types of observable variation change in response to environmental exposures, thus seeming open to the possibility that the generation of variation might be environmentally responsive [ 1 ]. However, even once mutations were described on a molecular level, many continued to treat spontaneous mutations as necessarily chance occurrences—typically as mistakes occurring during DNA replication or repair. Darwinian evolution, however, requires only two things: heritable variation (usually genetic changes) and selection imposed by the environment. Any of many possible modes of mutation—purely “chance” or highly biased, regulated mechanisms—are compatible with evolution by variation and selection.

Here, we review some of the wealth of evidence, much of which originated in microbes, that reframes mutagenesis as dynamic and highly regulated processes. Mutation is regulated temporally by stress responses, occurring when organisms are poorly adapted to their environments, and occurs nonrandomly in genomes. Both biases may accelerate adaptation.

Bacteria teach biologists about evolution

Microbes were initially held as proof of the independence of mutational processes and selective environments. The Luria–Delbruck experiment (1943) demonstrated that bacterial mutations to phage resistance can occur prior to phage exposure [ 2 ], and the Lederbergs showed similar results for resistance to many antibiotics [ 3 ]. However, discovery of the SOS DNA-damage response and its accompanying mutagenesis [ 4 – 7 ] in the post-DNA world of molecular genetics began to erode the random-mutation zeitgeist. Harrison Echols thought that the SOS response conferred “inducible evolution” [ 8 ], echoing Barbara McClintock’s similar SOS-inspired suggestion of adaptation by regulated bursts of genome instability [ 9 ]. But SOS mutagenesis might be an unavoidable byproduct of DNA repair, and high-fidelity repair might be difficult to evolve, many argued. John Cairns’ later proposal of “directed” or “adaptive” mutagenesis in starvation-stressed Escherichia coli [ 10 , 11 ] reframed the supposed randomness of mutation as an exciting problem not yet solved. The mutagenesis they studied under the nonlethal environment of starvation is now known to reflect stress-induced mutagenesis—mutation up-regulated by stress responses. Its molecular mechanism(s), reviewed here, demonstrate regulation of mutagenesis. Similar mechanisms are now described from bacteria to humans, suggesting that regulated mutagenesis may be the rule, not the exception (discussed here and reviewed more extensively, [ 12 ]).

Stress-induced mutagenic DNA break repair in E . coli

DNA double-strand breaks (DSBs) occur spontaneously in approximately 1% of proliferating E . coli [ 13 , 14 ]. In unstressed E . coli , DSB repair by homologous recombination (HR) is relatively high fidelity. However, activation of the general stress response, for example, by starvation, flips a switch, causing DSB repair to become mutagenic [ 15 , 16 ]. This process of mutagenic break repair (MBR) causes mutations preferentially when cells are poorly adapted to their environment—when stressed—and, as modeling indicates [ 17 – 20 ], may accelerate adaptation.

At least three stress responses cooperate to increase mutagenesis in starving E . coli . The membrane stress response contributes to DSB formation at some loci [ 21 ]; the SOS response up-regulates error-prone DNA polymerases used in one of two MBR mechanisms [ 22 – 24 ]; and the general stress response licenses the use of, or persistence of errors made by, those DNA polymerases in DSB repair [ 15 , 16 ]. The requirement for multiple stress responses indicates that cells check a few environmental conditions before flipping the switch to mutation [ 25 ]. E . coli MBR is a model of general principles in mutation from bacteria to human: the regulation of mutation in time, by stress responses, and its restriction in genomic space, limited to small genomic regions, in the case of MBR, near DNA breaks. We look at MBR, then other mutation mechanisms in microbes and multicellular organisms, which share these common features.

MBR mechanisms

Two distinct but related MBR mechanisms occur in starving E . coli , and both require activation of the general/starvation response. Moreover, both occur without the starvation stress if the general stress response is artificially up-regulated [ 15 , 16 ], indicating that the stress response itself without actual stress is sufficient. Homologous-recombinational (homology-directed) MBR (HR-MBR) generates base substitutions and small indels via DNA-polymerase errors during DSB-repair synthesis ( Fig 1A–1F ). Microhomologous MBR causes amplifications and other gross chromosomal rearrangements (GCRs) [ 26 – 28 ], most probably by microhomology-mediated break-induced replication (MMBIR) [ 28 , 29 ] ( Fig 1A–1C , 1G and 1H ). Both MBR pathways challenge traditional assumptions about the "chance" nature of mutations.

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(a–c) RecBCD nuclease loads RecA HR protein onto ssDNA, similarly to human BRCA2 loading RAD51; basepairing with a strand of identical duplex DNA (gray, e.g., a sister chromosome). Parallel lines, basepaired DNA strands. Repair synthesis (dashed lines) is switched to a mutagenic mode by the general stress response (sigma S). DNA polymerase errors (d, purple X) generate indels (e, purple XX) and base substitutions (f, purple XX). Microhomologous MBR requires DNA Pol I for template switching to regions containing microhomology (g), of as little as a few basepairs, and initiates replication, creating genome rearrangements; (h) a duplicated chromosome segment (blue arrows) is shown here. Circled numbers and shading indicate the three main events in HR-MBR: ① a DSB and its repair by HR, ② the SOS response (pink), and ③ the general stress response (blue). Note that HR-MBR (d–f, purple) requires both the SOS response (②, pink, which up-regulates error-prone DNA Pol IV, necessary for HR-MBR) and general stress response (③, blue), but microhomologous MBR (g–h, blue) requires the general stress response but not SOS (③, blue). Figure modified from [ 12 ]. HR, homologous recombination; MBR, mutagenic break repair; ssDNA, single-stranded DNA.

https://doi.org/10.1371/journal.pgen.1007995.g001

Both MBR mechanisms are initiated by a DSB and require HR DSB-repair proteins ( Fig 1 , ①) [ 15 , 28 , 30 – 33 ]. The first steps mirror standard HR DSB repair: RecBCD nuclease processes DSB ends and loads RecA HR protein ( Fig 1A and 1B ). Next, the RecA–DNA nucleoprotein filament can activate the SOS response ( Fig 1 , ② pink), which is required for HR-MBR but not microhomologous MBR. RecA also facilitates strand invasion—the initial contact between the broken DNA molecule and an identical sister chromosome from which repair is templated ( Fig 1C ). In unstressed cells, this intermediate leads to high-fidelity HR repair; however, if the general stress response is activated, repair proceeds via one of two mutagenic pathways ( Fig 1D–1H , ③). In HR-DSB repair, errors generated by error-prone SOS-up-regulated DNA polymerases IV (DinB), V (UmuDC), and II (PolB) accumulate in the tracts of repair synthesis during HR repair ( Fig 1D ) [ 22 , 23 , 34 ]. Activation of the general stress response licenses the use of these polymerases and/or prevents the removal of errors they generate: base substitutions and small indels ( Fig 1E, 1F ) [ 35 , 36 ] that are located mostly in clusters/hotspots of about 100 kb around the original DSB location [ 30 ]. Microhomologous MBR requires DNA Pol I, which is proposed to promote microhomology-dependent template switching during repair synthesis to generate GCRs ( Fig 1G and 1H ) [ 28 ]. Similar MMBIR mechanisms are proposed to underlie many DSB-driven GCRs in human genetic diseases and cancers [ 28 , 29 , 37 ].

Stress response regulation of E . coli MBR

Environmentally responsive and temporally regulated MBR mechanisms challenge long-held assumptions about the constant, gradual nature of mutagenesis and its blindness to an organism’s environmental suitability, or the lack of it, showing that mutagenesis is regulated tightly via environmental inputs. The general stress response controls the switch between high-fidelity or mutagenic DSB repair [ 15 , 16 ]. This stress response, controlled by the alternative sigma factor σ S , is activated by starvation, cold, acid, antibiotic, oxidative, and osmotic stresses, among others. During a general stress response, the σ S transcriptional activator increases the transcription of hundreds of genes (approximately 10% of all E . coli genes) that provide a range of protective functions (reviewed, [ 38 ]). We do not know exactly how the general stress response promotes mutagenesis. Two possibilities are as follows. First, the general stress response modestly up-regulates error-prone Pol IV above SOS-induced levels [ 39 ]. This might be the rate-limiting step. Also, the general stress response down-regulates mismatch repair (MMR) enzymes MutS and MutH [ 40 , 41 ]. The HR-MBR mutation spectrum is similar to that of unstressed MMR-deficient strains [ 35 , 36 , 42 ], suggesting that MMR becomes limiting transiently during HR-MBR [ 36 , 43 , 44 ]. Other σ S targets are also plausible, including down-regulation of the high-fidelity replicative DNA Pol III. Together, these observations suggest a model in which the general stress response enables error-prone polymerases to participate in DSB repair and/or allows the errors introduced by these polymerases to escape mismatch repair.

At least two other stress responses also contribute to one or both MBR mechanisms. The SOS DNA-damage response is required for HR-MBR [ 45 ] but not microhomologous MBR [ 22 ]. The SOS response is detected in about 25% of cells with a reparable DSB [ 13 ] and so comes automatically with the DSB that initiates MBR. (The 75% without SOS may repair fast enough to avoid SOS [ 13 ].) The SOS response halts cell division and activates DNA-damage tolerance and repair pathways. The primary role of the SOS response in HR-MBR is the upregulation of the error-prone DNA polymerases IV and V and possibly II. In some assays, production of Pol IV completely restores mutagenesis in SOS-defective cells [ 23 ]. In others, Pols II and V also contribute to mutagenesis [ 16 , 34 , 46 ]. Finally, the membrane stress response, regulated by σ E , promotes MBR at some loci by playing a role in spontaneous DSB formation through an unknown mechanism (see “Localization of MBR-dependent mutations”) [ 21 ]. The membrane stress response is triggered by an accumulation of unfolded envelope proteins caused by heat and other stressors [ 47 ] and therefore appears to couple these stressors to mutagenesis.

A genome-wide screen revealed a network of 93 genes required for starvation stress–induced MBR [ 25 ]. Strikingly, over half participate in sensing or signaling various types of stress and act upstream of activation of the key stress response regulators, which are hubs in the MBR network. During starvation stress, at least 31 genes function upstream of (in activation of) the general stress response. Most encode proteins used in electron transfer and other metabolic pathways, suggesting that these may be the primary sensors of starvation stress. Additionally, at least six genes are required for activation of the SOS response during MBR, and at least 33 MBR-network genes are required for activation of the membrane stress response. The 93 MBR genes form a highly connected network based on protein–protein interactions with the three stress response regulators (σ S , RecA/LexA, and σ E ) as nonredundant network hubs [ 25 ]. The MBR network highlights the importance of tight, combinatorial stress response regulation of mutagenesis in response to multiple inputs.

Generality of general stress response–promoted mutation

In E . coli , σ S -dependent mutagenesis has a mutational signature that is distinct from that seen in low-stress mutation accumulation (MA) studies and generation-dependent mutagenesis [ 34 , 35 , 42 , 48 ]. Importantly, the nucleotide diversity in genomes of extant E . coli and other bacteria is described better by the σ S -dependent signature than the signature seen in MA studies [ 48 ]. Specifically, both σ S -dependent mutations and those seen in extant species have much higher ratios of transitions to transversions than is seen in MA experiments or expected by chance. This suggests that a significant portion of adaptive mutations in bacteria arise from σ S -dependent stress-induced mutation mechanisms such as MBR [ 48 ]. Furthermore, mathematical modeling suggests that stress response–regulated mutagenesis, such as MBR, promotes adaptation in changing environments [ 17 – 20 ]. Organisms that encode regulated mutagenesis mechanisms may have an increased ability to evolve, which would promote the evolution and maintenance of such mechanisms by second-order selection [ 17 , 19 , 20 ].

Localization of MBR-dependent mutations

MBR generates mutations in hotspots close to the site of the instigating DSB, not at random locations in the genome [ 30 , 49 ]. Hotspotting near DSBs is best described for HR-MBR initiated by engineered DSBs at various sites in the bacterial chromosome [ 30 ]. Mutations are most frequent within the first kilobase (kb) pair on either side of the DSB, and then fall off to near background levels approximately 60 kb from the break, with a weak long-distance hot zone of around 1 MB from the DSB site. This pattern of mutations supports the model that most MBR-dependent mutations arise from DNA polymerase errors during HR repair synthesis, and the remainder arise during more processive error-prone break-induced replication. The observation that mutations occur near DSBs does not, in itself, suggest that mutations are more likely to occur in certain genomic regions or in locations related to an organism’s adaptive “need.” However, it does suggest that the distribution of mutations is likely to mirror the distribution of DSBs, and the following lines of evidence suggest that DSB distributions may be nonrandom and reflect potential utility of genes in particular environments.

The sources and distributions of spontaneous DSBs are poorly understood in all organisms (reviewed, [ 14 ]), but we have some clues about the origins of DSBs that lead to MBR. First, transcriptional RNA–DNA hybrids (R-loops) are one source of MBR-promoting DSBs [ 50 ]. R-loops have been implicated in DSB formation in many experimental systems, although the exact mechanism(s) of DNA breakage is unresolved (reviewed, [ 51 ]). Though the distribution of R-loops has not been thoroughly assessed in starving E . coli , R-loops tend to be biased toward highly transcribed genes, promoters, and noncoding-RNA genes [ 52 – 54 ] and might, therefore, target DSBs and mutations to those sites. Also, activation of the σ E membrane stress response is required for DSB formation in some assays and might target DSBs in genomic space [ 21 ]. The mechanism by which the σ E stress response causes DSBs is unknown, but one possibility is that σ E -activated transcription causes DSBs directly (rather than via gene products’ up- or down-regulation), via an R-loop–dependent or other transcription-dependent mechanism. R-loops and the σ E stress response might direct DSBs, and thus mutations, to regions of the genome with more adaptive potential for a given environment: transcribed genes and regulatory elements (promoters and regulatory small RNAs).

Additionally, MBR-dependent mutations can occur in clusters [ 55 ]. When a MBR-induced mutation occurs, the probability of finding another mutation at neighboring sites 10 kb away is approximately 10 3 times higher than if the first mutation did not occur [ 55 ], and this is not true for a distant unlinked site in the genome [ 43 ], indicating that nearby mutations are not independent events. That is, linked mutations appear to occur simultaneously, in single MBR events. Such clusters are predicted to promote concerted evolution by simultaneously introducing changes to multiple domains of a protein or subunits of a complex protein machine [ 15 , 20 , 55 ]. Because multiple mutations are often needed for new functions to emerge, and often, the intermediate mutated states are less fit and counter selected, how complex protein machines evolve has been a long-standing problem [ 56 ]. Similar clusters have been identified in many organisms [ 57 ] and in cancer genomes, in which mutation clusters are called kataegis , Greek for (mutation) storms [ 58 – 60 ]. The mechanisms of mutation localization and co-occurrence revealed by MBR in E . coli have guided more mechanistic understanding of how mutation clusters occur across the tree of life.

Analyses of E . coli mutation accumulation lines and natural isolates indicate that local mutation rates vary by about one order of magnitude on the scale of approximately 10–100 kb [ 61 , 62 ]. It is possible, even likely, that the DSB-dependent mutation localization and co-occurring mutation clusters characteristic of MBR are important contributors to this nonuniformity in mutation rate. Similar degrees of variation in local mutation rates have been reported for other bacteria [ 63 ], yeast [ 64 ], and mammals (mouse, human, and other primates [ 65 , 66 ]) and could also result from MBR-like mutation mechanisms. Further analysis of natural isolates, with a specific focus on identifying clusters of cosegregating single-nucleotide variants, could indicate how frequent MBR-dependent mutation clusters are and how they shape genomes.

The molecular mechanisms of MBR reveal many ways by which mutations do not occur uniformly or independently from one another in genomic space. More work is needed to assess fully whether the MBR mechanism or genomes themselves have evolved to bias mutations to locations where they are most likely to be beneficial, such as genes actively transcribed in response to the experienced stressor.

Other regulated mutagenesis mechanisms in microbes

In addition to starvation-induced MBR in E . coli , diverse bacteria and single-celled eukaryotes display examples of stress response–up-regulated mutagenesis. Some of these mutation mechanisms provide additional insight into how mutation rates vary across genomes in ways that may accelerate adaptive evolution. Many share characteristics with E . coli MBR but differ enough to suggest that regulated mutagenesis has evolved independently multiple times, thus highlighting the importance of regulated mutagenesis to evolution-driven problems, such as combatting infectious disease and antimicrobial resistance. Potential strategies to counteract pathogen evolution require understanding of how genetic variation is generated in these organisms. Continued study of regulated-mutagenesis mechanisms may reveal potential new drug targets to block mutagenesis and thus evolution [ 12 , 25 , 67 ].

Other mechanisms of starvation stress–induced mutagenesis in bacteria

Diverse wild E . coli isolates show increased mutation rates during extended incubation on solid medium compared with vegetative growth, known as mutagenesis in aging colonies (MAC) [ 68 ]. In the one isolate tested for genetic requirements, MAC required σ S , decreased MMR capacity and error-prone Pol II but not DSB-repair proteins or SOS activation [ 68 ]—like, but not identical to, MBR in E . coli . Bacillus subtilis undergoes starvation-induced mutagenesis that is up-regulated by the ComK starvation-stress response and requires the SOS-induced Pol IV homolog YqjH but does not require DSB repair [ 69 , 70 ]. In B . subtilis , starvation-induced mutation of reporter genes increases with increased levels of transcription of those genes, dependently on the transcription-coupled repair factor Mfd [ 71 ], similarly to E . coli MBR [ 50 ]. This suggests that transcription directs starvation-induced mutations to transcribed regions of the B . subtilis genome, where they are more likely to be adaptive. This is similar to the hypothesized targeting of E . coli MBR but occurs through a DSB-independent mechanism.

Antibiotic-induced mutagenesis in bacteria

Many antibiotics, especially at subinhibitory concentrations, increase mutation rate and generate de novo resistance and cross-resistance in a variety of bacteria, including important pathogens. The β-lactam antibiotic ampicillin induces mutagenesis in E . coli , Pseudomonas aeruginosa , and Vibrio cholera via a mechanism requiring σ S , Pol IV, and limiting mismatch repair [ 41 ]. Whether DSBs are involved remains untested. The topoisomerase-inhibiting antibiotic ciprofloxacin (cipro) induces cipro resistance rapidly in E . coli , requiring HR proteins, SOS induction, and error-prone Pols II, IV, and V [ 72 ]. A requirement for σ S has only very recently been demonstrated, along with the demonstration that cipro-induced mutagenesis is σ S -dependent MBR, similar to that induced by starvation[ 73 ]. In fact, diverse antibiotics both create DSBs [ 74 ] and activate the general stress response in E . coli [ 41 ], suggesting that these antibiotics may increase mutagenesis both by increasing DNA damage and triggering a switch to low-fidelity repair of that damage.

Stress response regulation of mobile DNA elements in bacteria

Environmental stress up-regulates the activity of mobile DNA elements in many organisms, and this inducible genome instability is likely to be an important driver of evolution (reviewed, [ 75 ]). Although the mechanisms of regulation are poorly understood, stress response regulators have been implicated in a few cases. The general stress response promotes excision of an E . coli transposable prophage [ 76 ] and a Pseudomonas transposon [ 77 ]. Starvation increases the retromobility of Lactobacillus lactis LtrB group II intron through signaling by the small molecule regulators guanine pentaphosphate (ppGpp) and cyclic adenosine monophosphate (cAMP) [ 78 ]. Mobility of an E . coli transposon is increased by metabolic disruptions and negatively regulated by the σ E membrane stress response [ 79 ]. Also, stress can directly regulate mobile element activity without an intervening stress response: movement of the T4 td intron becomes promiscuous during oxidative stress through ROS-induced oxidation of an amino acid in the intron-encoded homing endonuclease, which makes it a transposase [ 80 ].

Regulated mutagenesis in eukaryotic microbes

Many examples of stress-associated mutagenesis and MBR have been reported in yeast, but stress response regulation has been demonstrated in only two cases. First, in the budding yeast Saccharomyces cerevisiae , the proteotoxic drug canavanine induces mutagenesis dependently on the MSN environmental stress response [ 81 ]. MSN-dependent mutagenesis requires the nonhomologous end-joining (NHEJ) protein Ku and two error-prone polymerases, Rev1 and Pol zeta (ζ) [ 81 ]. NHEJ is a relatively genome-destabilizing DSB-repair pathway, so MSN-dependent mutagenesis represents a stress-induced switch to MBR. NHEJ proteins are required for starvation-induced mutations in yeast as well [ 82 ]. Others have reported yeast MBR dependent on the error-prone DNA polymerase Rev3 [ 83 ] and spontaneous mutations dependent on error-prone polymerases Rev1 and Pol ζ [ 84 ]. Yeast also form mutation clusters by MBR [ 85 ] and undergo MMBIR similar to E . coli microhomologous MBR [ 86 ]. It is unknown whether these observations represent one or more mechanisms of mutation and whether MSN or other stress responses regulate mutagenesis in these cases. In all cases of yeast MBR, mutations are likely to occur near DSBs and, therefore, may be localized within genomes, as discussed for E . coli MBR.

Second, a heat shock response, activated by heat shock or protein denaturation, induces aneuploidy in S . cerevisiae by titration of the chaperone heat shock protein 90 (HSP90) [ 87 ]. Inhibitors of HSP90, such as radicicol, also induce aneuploidy. HSP90 is required for proper folding of kinetochore proteins in unstressed cells, so HSP90 titration or inhibition probably triggers aneuploidy through the disruption of kinetochore assembly [ 87 ]. The resulting yeast cell populations show high karyotypic and phenotypic variation and harbor cells resistant to radicicol and other drugs [ 87 ]. Aneuploidy in the form of extra chromosome copies may also facilitate adaptive evolution by providing a larger mutational target. Extra chromosomes may also buffer otherwise deleterious mutations through the sharing of gene products. Similar heat- and other stress-induced aneuploidy has been reported in Candida albicans and other yeast species, and can cause resistance to a variety of compounds, including clinically relevant antifungal drugs (reviewed, [ 88 ]). Some of these examples are likely to result from HSP90 titration, but other stress responses may be involved also.

Regulated mutagenesis in multicellular organisms

Although microbes led the way in revealing mechanisms of stress response–up-regulated mutagenesis, many microbial mutation mechanisms are mirrored throughout the tree of life, including in multicellular organisms. Stress response–up-regulated mutation mechanisms have been discovered in plants, flies, and human cells (reviewed, [ 12 ]). The potential adaptive roles of these mutation mechanisms are less clear in multicellular organisms than in microbes. Do these mechanisms contribute to germline variation (and thus organismal evolution), mosaicism and somatic cell evolution, or both? Or are they simply biproducts of other required cellular functions or stress-induced dysfunctions?

In the Drosophila germline, the HSP90 heat shock response increases transposon-mediated mutagenesis and can drive organismal adaptation [ 89 ]. Most other regulated mutation mechanisms characterized to date have been in somatic cells, in which they might contribute to mosaicism. Somatic diversity may be important during development and contribute to organismal fitness, as is the case with antibody diversification during B-cell maturation. For example, neural development might require genetic complexity and plasticity as organisms get differently “wired” during development, based on their experiences. However, up-regulated mutagenesis is also likely to drive pathogenic somatic evolution, such as during cancer development. For example, hypoxic stress responses trigger down-regulation of mismatch repair and down-regulate HR DSB-repair proteins RAD51 and BRCA1, leaving only chromosome-rearranging nonhomologous or microhomologous DSB-repair mechanisms (reviewed, [ 90 ]). Hypoxic stress response–induced mutagenesis occurs in mouse and human, suggesting an adaptive function in addition to its probable relevance to tumor biology. Tumors become hypoxic and induce hypoxic stress responses, which promote angiogenesis. Hypoxic stress responses may also promote tumor evolution via mutagenesis. The tumor growth factor β (TGF-β) signaling pathway also induces genome rearrangement by reduction of HR DSB repair in human cancer cell lines, leading to increased copy number alterations and resistance to multiple chemotherapeutic drugs [ 91 , 92 ]. Stress-induced and localized mutagenesis in multicellular organisms and the relevance of these mechanisms to cancer are reviewed in more detail elsewhere [ 12 ].

Evolution and applications of stress-induced mutation

Mutations provide the raw material for evolution but can also decrease the fitness of an organism. Therefore, mutation rates have, presumably, been finely tuned, apparently through second-order selection. Constitutively high mutation rates are advantageous in rapidly changing environments but decrease fitness in more stable (or periodically changing) environments. By biasing mutation to times of stress and to particular genomic regions, perhaps such regions relevant to a specific stress, stress-induced mutagenesis mechanisms provide the benefits of high mutation rate, while mitigating the risks. The ubiquity of these mechanisms throughout the tree of life supports their crucial role in evolution.

Stress-induced mutation mechanisms, first discovered in bacteria, challenge historical assumptions about the constancy and uniformity of mutation but do not violate strict interpretations of the Modern Synthesis. Mutation is still viewed as probabilistic, not deterministic, but we argue that regulated mutagenesis mechanisms greatly increase the probability that the useful mutations will occur at the right time, thus increasing an organism’s ability to evolve and, possibly, in the right places. Assumptions about the constant, gradual, clock-like, and environmentally blind nature of mutation are ready for retirement.

Stress-induced mutation mechanisms are likely to play important roles in human disease by promoting pathogen and tumor evolution and may drive evolution more generally. Mutation mechanisms may also be attractive drug targets for combatting infectious disease, cancer, and drug-resistance evolution in both [ 73 ]. Although many mechanisms of stress-inducible mutation have been identified in the past two decades [ 12 ], these are likely to be the tip of the iceberg. Some current pressing questions are highlighted below.

Open questions in mutation research

• What fraction of total “spontaneous” mutagenesis results from mutagenesis up-regulated by stress responses? Do stress response–regulated mutation programs drive much of adaptive evolution in microbes? Multicellular organisms?
• Are DSBs and the mutations they cause randomly distributed in genomic space? Or is DSB formation regulated, biased, or directed? By what mechanisms? Is this targeting adaptive?
• Can stress response–regulated mutation mechanisms be targeted by anti-evolvability drugs that limit the generation of heritable diversity? Can these drugs prevent pathogens and cancers from out-evolving host responses and drugs?

Acknowledgments

We thank P.J. Hastings for comments on the manuscript and our colleagues in this bundle for extreme patience.

• 1. Darwin CR. On the origin of species by means of natural selection, or the preservation of favoured races in the struggle for life. London: John Murray; 1859.
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• 6. Radman M. Phenomenology of an inducible mutagenic DNA repair pathway in Escherichia coli : SOS hypothesis. In: Prokash L, Sherman F, Miller M, Lawrence C, Tabor H, editors. Molecular and Environmental Aspects of Mutagenesis. Springfield, Illinois: Charles C. Thomas; 1974. p. 128–42.
• 7. Radman M. SOS Repair Hypothesis: Phenomenology of an Inducible DNA Repair Which Is Accomplanied by Mutagenesis. In: Hanawalt P, editor. Molecular Mechanisms for Repair of DNA. New York: Plenum Press; 1975.
• 73. Pribis JP, García-Villada L, Zhai Y, Lewin-Epstein O, Wang A, Liu J, et al. Gamblers: an antibiotic-induced evolvable cell subpopulation differentiated by reactive-oxygen-induced general stress response. Molecular cell. 2019;74 (in press). https://doi.org/10.1016/j.molcel.2019.02.037

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2024 Question

Many human diseases have a genetic component. Some diseases result from a change in a single gene or even multiple genes. Yet, many diseases are complex and stem from an interaction between genes and the environment. Environmental factors may include chemicals in the air or water, nutrition, microbes, ultraviolet radiation from the sun and social context. Provide an example of how the interplay of genetics and environment can shape human health.

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Essay on Mutation | Biology

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In this essay we will learn about Mutation. After reading this essay you will learn about: 1. Meaning of Mutation 2. Gene Mutation 3. Chromosomal Aberrations.

• Essay on Chromosomal Aberrations

Essay # 1. Meaning of Mutation:

Mutation of a plant or an animal means a sudden change in its hereditary make-up. Suddenly a mutated organism arises and the changed or mutated appearance is usually found to be hereditary, i.e., it breeds true. Since heredity is controlled by genes, it follows that the genes somehow change their behaviour.

While mutations are always taking place is nature very few of them are of a major nature to be readily apparent. In many cases, the changes are so minor that they are not readily apparent while in most cases they are recessive and remain latent.

The de Vriesian concept of mutation has changed now as many changes which were considered as fluctuating variations by Darwin and de Vries have been found to be true mutations of a minor nature.

The actual change in the genes may be of two types:

(I) Intragenic or

(II) Intergenic.

I. Intragenic change means something has happened within the gene itself or the gene has mutated, i.e., it has undergone some chemical or structural change. Since the gene itself has mutated this may be called gene mutation which is sometimes considered as the true type of mutation. Gene mutation is also called point mutation since the mutation has taken place at a point or locus on the chromosome.

II. Intergenic changes involve merely the rearrangement of the genes already existing or the loss of some of them. So, this type of mutation does not involve the formation of mutated genes.

They are chromosomal mutations or chromosomal aberrations which are caused either (A) by a change in the number of chromosomes which may involve either individual chromosomes (aneuploidy) or whole sets of genomes (euploidy), or (B) by a change in the structure of chromosolies.

Essay # 2. Gene Mutation:

As we come across a really mutated gene only in this type of mutation, sometimes the word mutation is applied to gene mutation or point mutation alone. In nature, genes are constantly duplicating themselves. Every cell division means the formation of new genes—daughter genes from mother genes. In this duplication the original gene is gene­rating an exact replica of itself.

But it is possible that while this process is going on for millions of times, once a while something may go wrong and the new gene may not be an exact replica of the original.

The gene, formed of nucleoproteins, must have a com­plex molecular structure and there may be a slight change somewhere. This change, however small it may be, gives rise to a mutated gene whose behaviour is different from its predecessors in some degree. Such spontaneous gene mutations are always occurring in nature.

Among some 10 million specimens of Drosophila melanogaster examined, a few hundreds of gene mutants were observed. These mutants give rise to true-breeding stable genotypes varying in some characters (eye colour, wing type, etc.) from the original wild type. Mutations like these are always observed in all types of organisms from human beings to bacteria. They arise all on a sudden.

Most mutations bring about such a minute change that they evade common observation. Moreover, most mutations are recessive as well as lethal. They produce no effect before appearing in a homozygous form in some future generation. They are, therefore, undetectable. However, there are some special cytogenetical methods (e.g., the CIR method) for detecting lethal muta­tions in X chromosomes of Drosophila.

CIB Method :

In this method of detecting lethal mutations in the X chromosomes of Drosophila the irradiated male fly is first crossed with a female of a special stock called CIB.

In this, of the two X’s of the female, one is normal (shown by the thick bar in the figure) while the other contains C (an inverted segment of chromosome), 1 (a lethal gene which cannot act being dominated by the normal X homologue which has no lethal) and B (bar-eye character) one fourth of the offspring would be female with one treated X (shown by a thick bar in the figure) and one CIB X, one fourth would be male with one CIB X which would die and half would be normal.

Only the female from the first quarter is crossed with a normal male in a second cross. Among the off-springs all males would die if a lethal gene has been induced. If no lethal gene has been induced there would be 2: 1 female to male (Fig. 864).

Mutations may affect every imaginable character in every possible way. Most mutations are harmful, possibly because they disturb the genie balance.

The rate of mutation of genes has been studied. This is different for different genes. While some genes are highly stable and do not mutate easily, there are others which are remarkably unstable.

Among such unstable genes mention may be made of the gene c in chromosome IX of maize causing a colourless aleurone in the grain which was found by Jones to easily mutate into the dominant C developing colour so that such mutations in the somatic aleurone cells give rise to spots on the grain.

Similarly the rose-a and lavender-a genes in Delphinium (Larkspur) were found by Demerec to mutate into purple giving rise to purple patches on the otherwise rose or lavender petals. This mutation may also take place on the germ cell giving rise to a fully purple-flowered mutation.

The stability of genes seem to be different in different species. In Drosophila the possibility of mutation of a gene has been calculated as 1 in 10 5 , in higher organisms 1 in 10 6 . In maize the rate of mutation of the R gene is of the order 492 in 1.5 X 10 5 while the same for the I gene is 10 6 , for the S gene 1 and for the Wx gene none. Haldane had cal­culated the rate of mutation in human beings as 1 to 5 in 10 6 .

If this be the rate of muta­tion of a single gene, the possibility of a mutation in an individual is great considering that there are thousands of genes in a cell. It has been suggested by Muller that there is some mutation in one out of every 20 gametes in Drosophila and in human beings there is a possibility of having one mutated gamete out of every 10.

The rate of mutation has been found to be affected by environmental and other factors viz., it increases with temperature and with age. The effect of X-rays and other ionising radiations is dis­cussed later. The rate of mutation may even be affected by other genes in the same cell.

Rhoades has shown that the Dt gene in chromosome IX of maize causes the gene in chromosome III to mutate into A 1 so that colourless plants show purple streaks on leaf and purple dots in aleurone.

Mutations may take place in somatic cells as well as in germinal cells. While the latter gives rise to mutate seeds and mutated progenies, the former, as seen above, gives rise to patches of tissues with mutated cells. Some such tissue may develop buds and shoots and bud sports or bud mutations arise in this way.

When vegetatively propagated, these buds may give rise to clones of mutated plants. Many agricultural and horticul­tural varieties have arisen in this way. Washington Navel orange plants are known to give rise to single mutated fruits as a result of somatic mutation just before the deve­lopment of the flower bud.

Although most of the mutations are useless and even harmful, sometimes a mutant may be of some biological value and they certainly play a great part in the evolution of new species. Many new breeds of domesticated animals and strains of cultivated crops must have arisen by gene mutation.

Different breeds of sheep (e.g., the short-footed Ancon sheep), swine, rats, horses, dogs, pigeons, etc., are known to have arisen in this way.

The Shirley poppy, the dwarf ‘ Cupid ‘ sweet pea and many varieties of showy flowers also arose by gene mutation. The cultivated Cicer gigas arose as a mutation of the common gram, Cicer arietinum (Fig. 865). Among cereals, an ageotropic mutant called ‘lazy’ (Fig. 866) is very common.

Different types of lethals, part lethals, chlorophyll deficiencies and albinos (human as well as in many animals like elephants, tigers, snakes etc.) are common and well-known instances of gene mutation.

Induction of Gene Mutation:

Since environmental factors are known to affect the rate of gene mutation. Naturally, they have been employed for the artificial induction of mutations.

Although attempts at induction of such mutation had been made before and Morgan had obtained some Drosophila wing mutants by radium treatment, the first concentrated work was by Muller who published in 1927 his work on X-ray induced mutations in Drosophila, a work for which he was awarded a Nobel Prize in 1946. This was followed by Stadler’s work on barley and then spread to other fields.

The most important mutagenic agents have been found to be ionising radiations, viz., α- (projected nuclei of helium atoms), β- and y- radiations of radioactive substances; X-rays; neutrons (projected electrically neutral particles, mainly from hydrogen nuclei) and protons.

All these act by ionising the atoms of the matter through which they pass so that they eject electrons. The ejected electrons, in their passage through matter, cause further ionisation losing energy with each collision until they finally halt. The actual cause of mutation is still a matter of speculation. One theory is that mutation is caused by the direct ‘ hit ‘ of the ‘ target ‘ by electrons.

The other view holds the cause of mutation as indirect being resultant of the chemical and physical changes brought about in the molecules surrounding the genes. The a-, β -, y-and X-rays are measured in roentgen (r) units which are products of the strength of the rays and the duration through which they work.

It has been found that the rate of mutation is directly proportional to the amount of total radiation received (in r-units) by the cells and not to the strength or the duration (Fig. 867) alone and not even to the type of radiation employed.

Induction of mutation by radiation has been tried on all types of organisms. The resultant mutations are sometimes visible, sometimes latent, being apparent only in future generations as they mainly occur as recessive genes.

In Drosophila 80% of the mutated genes have been found to be of the lethal type. The same may be true for other organisms. Mutagenic treatments may ensure one of getting mutants but the type of resultant mutations cannot be predicted.

Induction of mutation has been tried on plant viruses and on bacteria with variable degrees of success. Among fungi, mutations have been induced in Neurospora.

There are numerous instances in higher plants—barley (Stadler and Gustafsson found hundreds of chlorophyll deficiencies and a few other types like the erectoid form), maize, tobacco, Antirrhinum, Oenothera, Datura, etc., and they have all been found to be equally responsive.

However, most spectacular results have been obtained in Drosophila.

Besides the, nume­rous recessive lethal genes (the X chromosome shows 1.5 lethal mutations in every thousand chromosomes per generation and this rate increases 70 times when the flies are subjected to a dosage of 4800 r-units) which are detectable only by adapting special cytogenetic techniques (c.f. CIB method), a large number of visible mutants have been obtained.

The most interesting of these are the eye colour mutants. White eye (w + ) mutates to eosin (w e ) and apricot (w a ) while coral (w co ), buff (w bf ), cherry (w ch ), apricot (w a ), eosin (w e ) and tinge (w t ) have been found to mutate to white. So the recessive white may also mutate to its dominants like eosin. These mutants are similar to the spontaneous mutations at the same locus.

Besides ionising radiations, non-ionising ultraviolet rays, chemical mutagens like those of the mustard gas group, and temperature have been found to be effective in inducing mutations but not to the same extent as the first.

Mustard gas (tried on Droso­phila, Neurospora and bacteria) has sometimes been found to be as effective as X-rays. Mutation rate generally increases with temperature but the rate of increase is different in different cases and there are some genes (specially the unstable ones) in which the mutation rate is lower in higher temperatures.

Multiple Allelomorphs:

Since the same gene may mutate again and again, and all such genes will remain at the same locus of the same homologous chromosomes, it is apparent that there may be a series of genes-occupying the same position. Then they will form a series of multiple allelomorphs, any two of which may act as an ordinary allelomorphic pair.

The presence of multiple allelomorphs helps to understand the nature of alleles and disproves the presence and absence hypothesis. Common examples of multiple allelomorphs are found in the anthocyanin genes of cotton, lice, maize, jute and in the eye colour genes of Droso­phila.

The eye colour of Drosophila is controlled by an allelomorphic series of at least twelve genes—Red wild type (W or +), white (w + ), ivory (w i ), pearl wP), tinged (w t ), buff (w bf ), honey (w h ), apricot (w a ), cherry (w ch ), eosin (w e ), blood (w b1 ) and coral (w co ). In cotton, the cultivated Old World cottons Gossypium arboreum and G. herbaceum show an allelic series of some 20 genes at the R 2 locus causing pigmentation of different plant organs and petals.

The New World cottons G. hirsutum and G. barbadense contain another series of alleles also controlling anthocyanin colouration at the R 1 locus in addition to R 2 . This proves the hypothesis that the New World cotton originated after hybridisation with the Old World cotton. A third similar allelic series of genes are known at the R 3 locus in G. anomalum.

In maize, the allelic series P in chromosome I, A 1 in chromosome III and R in chro­mosome X control anthocyanin colouration. In rice, at least two different allelic series C and Sp, located in two different chromosomes, seem to control anthocyanin colour­ation. In Jute, 5 alleles at the A locus, also controlling anthocyanin colouration, have become known.

Essay # 3. Chromosomal Aberrations:

These result from chromosomal aberration disturbing the normal number or structure of the chromosomes. Thus, they may also be called chromosomal mutations. In these, the gene disturbance is intergenic not involving their internal structures.

According as the aberration involves the number or the structure of the chromo­somes, these may be of two types:

A. Changes Involving Change in the Number of Chromosomes :

The number of chromosomes for every species of organism is fixed. In higher plants and animals the ordinary cells contain In number of chromosomes (i.e., two sets of the same genome) and the organisms are, therefore, called diploid. It is found that this fixed number may change causing a mutation into a new type. If such a change be suffi­ciently great and hereditary, then the mutant forms a new species.

Change in the number of chromosomes sometimes involves multiplication of the whole chromosome sets (genomes), i.e., the number, instead of being 2n, becomes 3n, 4n, 6n, etc. These are generally called Polyploids or true polyploids (Euploids).

Haploids (n) caused by a decrease in genomes, is usually considered along with the Euploids. In other cases, the change involves increase or decrease in the number of single chromo­somes and not of whole sets. Thus numbers like 2n-1 or 2n + 1 may be obtained. These are irregular polyploids or Heteroploids or Aneuploids.

Besides the above, some changes in the chromosome number may be caused by fusion of chromosomes, by breaking down of chromosomes or by formation of chromo- some-like bodies by inert material which may not contain any gene (supernumerary chromosomes, e.g., B-chromosomes of maize and m-chromosomes of mosses).

(a) Euploids or True Polyploids:

These again are of two types. Some involve the multiplication of exactly the same genome (Allopolyploid) while in others different types of genomes are involved (Allopolyploid). These polyploids have played an important role in the evolution of new species.

Many cultivated crops have developed from wild plants by means of allo­polyploidy. Sometimes a polyploid may be sterile but it may still be a very important agricultural or horticultural crop by vegetative propagation. Among animals, poly­ploids are rare.

Allopolyploids :

Cytological investigations have shown the presence of polyploid series among some cultivated plants Thus, Fig. 868 shows the chromosomes of diploid (2n), triploid (3n), tetraploid (4n), pentaploid (5n), hexaploid (6n) and octoploid (8n) rose. Fig. 869 shows the appearance of haploid (n), diploid, triploid and tetraploid Datura flowers.

Haploid (n):

Although not really polyploids, haploids are considered in connec­tion with them because they are members of the same polyploid series. Haploids usually occur as a result of parthenogenesis—whether spontaneous or induced.

They have been found in rice containing double embryos of which one is normal and the other is parthenogenetic. The stimulus of parthenogenesis may come from ineffective pollination when foreign pollen or X-rayed pollen is used in pollination.

Haploid plants have been found in a number of species like Datura stramonium, Oryzasativa, Oenotherasp., Triticum sp., Zea mays, etc. Haploid plants are all-round weak and small but there is a report of a haploid plant in pepper as healthy as a normal diploid. As there is only one set of chro­mosomes, there should be no pairing during meiosis so that normal pollens or eggs are not formed.

A normal gamete is possible only if by chance all the chromosomes remain at the equator and form a single nucleus during irregular meiosis. Haploids are, there­fore, usually sterile. In some cases, however, bivalents are noticed during meiosis. This indicates that in the original genome duplication of chromosomes was already present and the basic number of the species is actually less than the haploid number.

This throws a light on the origin of the species. Haploids may be utilised in cytogenetics in another way. By applying colchicine the chromosome set in the hap­loid may be doubled and normal diploid may be obtained. The diploid will be per­fectly homozygous—a condition rarely obtained in nature. Such a diploid plant is of great use in cytogenetics and plant breeding.

In the animal world, the males of bees, wasps and other Hymenoptera are normally haploid. They have adjusted their lives to this nature. There is no reduction during meiosis. There is no synapsis and either during the first division all the chromosomes normally pass to one pole or the first division is completely eliminated. The meiosis, therefore, is equational and normal sperms are formed.

Triploid (3n):

Autotriploids have been observed or obtained like the haploids in a number of plants like Oenothera, Datura, rose, rice and many others. Drosophila triploids are well known. Triploids are usually formed as a result of the fusion of a diploid gamete (formed abnormally) with a normal haploid one. Diploid pollens or eggs may come from tetraploid plants or sometimes occur abnormally under the influence of X-rays, etc.

As in the case of haploids, the three sets of genomes are unable to pair during meiosis so that functional gametes are rarely formed. As a result, triploid plants are usually sterile like the haploids. But, triploids may be useful in horticulture as, when propagated vegetatively, they have been found to develop seedless fruits in many cases. Triploid plants may or may not be bigger than normal diploids.

Tetraploids (4n):

Tetraploids are the most important of the polyploids. They are found widely in nature and may also be induced artificially. Numerous cultivated varieties have autotetraploid varieties along with normal diploids. Since the four sets of chromosomes may easily pair between themselves normal diploid gametes are formed which form normal tetraploid seeds.

During diakinesis one often sees tetravalents of chromosomes instead of the bivalents seen in normal diploids. Nevertheless, varying degrees of sterility are observed among tetraploids. Tetraploid plants are usually larger, more succulent and have bigger pollens, stomata, fruits, etc.

The succulence may render the tetraploid more susceptible to disease. Their relative sterility often precludes their use as commercial crops but the large size of fruits  etc. may be useful in horticulture. Tetraploids sometimes arise as somatic bud mutations. They have been obtained by the decapitation of tomato plants when the new shoots become tetraploid.

High temperature induces tetraploidy. But, the most popular method is treatment with chemicals, the most important of which is colchicine which has become extremely popular since its practical applica­tion by Blakeslee and by Nebel simultaneously in 1937.

Since then it has been applied to thousands of plants. Its application in liquid form or as jelly to seeds and growing tips is not very difficult although the results are not always certain. In the simplest cases, seeds soaked in dilute solutions germinate into tetraploid plants.

Colchicine prevents the: separation of daughter chromosomes after they have divided by arresting the formation of the spindle and forms nuclei with double the number of chromosomes (4n) during mitosis. As a result, a 4n tissue arises forming a diploid shoot.

Higher-ploids:

Pentaploids (5n), Hexaploids (6n), Octoploids (8n), etc., have also been found among wild and cultivated plants (e.g., rose in Fig. 868). All these show how the formation of new species is facilitated by polyploidy.

While the autopolyploids are formed by the multiplication of the same set of chromo­somes (genome) all the allopolyploids are formed by the union of different genomes from different plants.

A very interesting example of an allopolyploid obtained artificially is the Raphano- brassica (Fig. 870) obtained by Karpechenko (1927). He crossed Raphanus sativus (radish, 2n = 18) with Brassica oleracea (cabbage, 2n = 18).

The hybrid was intermediate between radish and cabbage and had 9 +9 (9R of Raphanus and 9B of Brassica) chromo­somes which did not pair during meiosis as they were from different plants. The hybrid was sterile. Accidentally, polyploidy occurred.

The 9R+9B chromosomed hybrid doubled its chromosomes (18R + 18B). Now, the chromosomes could pair between themselves and perfect seeds were formed. This pairing of chromosomes is autosyndesis as actually, chromosomes of similar genomes (R or B) are pairing with their respective homologues.

The 36 chromosomed final plant is a tetraploid but it is an allotetraploid as the 36 chromosomes are coming from two different genomes. This sudden doubling of chromosomes which formed the allotetraploid is called amphidiploidy.

Subsequently, it has been found that such amphidiploidy may be induced artifi­cially by colchicine. As a result, some hybrids which were sterile have been transformed into fertile allotetraploids by the induction of amphidiploidy.

An examination of the cultivated plants shows that allopolyploidy has played a very important role in the evolution of these species. Cytogenetical analysis of culti­vated wheat plants has yielded very valuable results. Investigations by Kihara and others show that the wheat species fall under three groups—diploid, allotetraploid and allohexaploid. These were formed from three different genomes.

The genome C is present in the grass Aegilops squarrosa (2n = 14) which grows wild in the region from Armenia to Afghanistan. Thus, in the evolution of the wheat species, one may suppose that Triticum monococcum (genome A) hybridised with another plant having genome B and also having 2n =14. There was amphidiploidy.

T. durum (2A + 2B, 2n = 28) resulted. Again, a member of the durum group hybridised with Aegilops squarrosa (genome C, 2n = 14) and an amphidiploidy gave T. aestivum (=vulgare) (2A + 2B + 2C, 2n = 42).

Actually two such hybridisations have been successfully done. Mcfaden and Sears obtained a wheat-like Triticum spelta (a member of the 42 chrvulgare group) by inducing amphidiploidy on a T. dicoccoides (a wild member of emmer group from the region Armenia to Palestine) X Aegilops speltoides hybrid.

Kihara has actually obtained a bread wheat similar to the cultivated T. aestivum (=vulgare) var. trythospermum hyamphidiploidising a T: persicum (a cultivated emmer wheat) x Aegilops squarrosa hybrid. It has now been established that the B genome has been derived from Aegilops speltoides. It is reasonable to suppose that the bread wheat originated in some place between Armenia, Persia and Afghanistan.

If the genome constitution of a natural species shows that it is an amphidiploid or allopolyploid, it may be possible to synthesise the species artificially. A very interesting example is that of Brassica juncea. Among culti­vated mustards there are three species —Brassica campestris (rape, 2n=20), Brassica nigra (black mustard, 2n = 16) and Brassica juncea (rai, 2n=36).

Genome analysis showed that the third species was an amphidiploid of the first two. Subsequently, a plant has been obtained synthetically by in­ducing amphidiploidy in the sterile Brassica campestris X Brassica nigra hy­brid (Fig. 872). This synthetic plant differs only slightly from natural Brassica juncea.

Segmental allopolyploids :

In the allopolyploids, it has been presumed that the chromosomes of the two parents have no affinities between themselves and so, there is absolutely no pairing between themselves. But, Stebbins is of opinion that in nature, in most allopolyploids there is some affinity between the chromo­somes of the two different genomes resulting in allosyndesis for some chromosomes.

During meiosis of these allopolyploids some tetravalents as well as some bivalents are seen and this results in some sterility. These have been named segmental allopolyploids and examples are found in Primula kewtruis (derived from P. floribunda x P. verticillata), Tradescantia canaliculata-himulis, Delphinum gyposophilum (derived from D. hesperium x D. recurvatum), etc.

(b) Aneuploids or Heteroploids or Irregular Polyploids:

In the aneuploids, one is concerned not with the multiplication of whole sets of chromosomes but with the increase or decrease of the number of homologues. Ordi­narily, two homologues of each chromosome are present in the diploid so that the chromosome number is 2n.

But, in exceptional cases there may be disturbances in the division of chromosomes so that the number of homologues instead of being two is changed to three (trisomic), four (tetrasomic) one (monosomic) or none (nullisomic).

Such disturbances may be spontaneous due to crossing between polyploids and heteroploids, different types of non-disjunction (aberration), incompatibility due to hybridisation between distant plants, etc., or may be induced by X-rays, etc. Aneuploids are usually sterile.

When aneuploids show an increase in chromosome number (e.g., 2n + 1) it may be called a hyperploid. When there is a decrease (e.g., 2n—1) it is a hypoploid.

Trisomies (2n + 1):

These are formed by the addition of an extra homologue of one chromosome. Many of the Oenothera ‘mutations’ found by de Vries are trisomics. Trisomies are widespread in nature and have been extensively studied in Datura and also in maize, tomato, wheat, Nicotiana and Drosophila. They are readily obtained by selfing a triploid or by crossing diploids with triploids.

Blakeslee and his students studied the Datura trisomies very closely and obtained 12 trisomies (Fig. 873) for the triplication of every one of the 12 chromosomes in Datura stramonium.

As can be seen from the figure, every one of the trisomies is distinct from the other. Besides these normal ones they also obtained other trisomies in which the three chromosomes were exactly alike, there being some segmental interchanges or trans­location. In a secondary trisomic the translocations are from the same chromosome.

Thus, while three 1 . 2 chromosomes give the rolled normal trisomic (Fig. 873), two l . 2 and one 1.1 gives sugarloaf and two 1 .2 with one 2.2 gives polycarpic.

In a secondary trisomic a closed ring (c.f.., Fig. 877) of the three chromosomes is possible. Ina tertiary trisomic, one of the three chromosomes contains a bit from a different chromosome. Thus, the trisomic hedge has one 1 . 9 chromosome (produced by translocation between 1.2 and 9.10) in addition to two l . 2 chromosomes.

Sears obtained trisomies in bread wheat (Triticum aestivum), but these do not differ much from the normal plants, possibly because the species is an allohexaploid.

A trisomic (47 instead of the 2n=46 chromosomes) mutation in human beings is known to cause the disease ‘Down’s syndrome’ (mongoloid features combined with mental slowness).

Double trisomic (2n + 1 +1) shows three homologues of each of two different chromosomes.

Tetrasomic (2n +2) has four homologues of the same chromosome. Sears obtained these as well in Triticum aestivum but these also do not differ from normal plants.

Monosomic (2n— 1):

There are two homologues of each chromosome excepting one of which there is one only. Apparently, the homologue of this chromosome is some­how lost. Monosomies arise in the same way as the trisomies but they are not usually viable. Datura monosomies are not viable. But, while the monosomic are not viable in true diploids, they have been successfully obtained in some allopolyploids.

In the allopolyploid Nicotiana tabacum (2n=48) Clausen and his colleagues obtained all the 24 possible monosomies and these are different from one another. Similarly Sears obtained all the 21 possible monosomies in Triticum aestivum (=vulgare) but these do not differ much from the normal. Monosomic analysis greatly facilitates assignment of genes to the linkage groups.

Nullisomic (2n—2):

In these plants, both the homologues of a particular chro­mosome somehow get lost so that the chromosome is completely missing from the plant. Such a plant should clearly show what genes were contained in the missing chromosome.

Nullisomic analysis, combined with monosomic, has greatly helped in determining linkage groups. Nullisomics are obtained by selfing monosomies. They are usually in-j viable like the monosomies. They are, however, known in maize and in Triticum aesti­vum (=vulgare) Sears obtained 17 of the 21 possible nullisomics.

B. Changes Involving Change in the Structure of Chromosomes :

Some accidents sometimes occur which end in the breaking-down of chromosomes. The broken bits may get healed up or get re-attached in a wrong way or may even get lost. These accidents are not to be confused with the normal crossing-overs.

Such inci­dents cause structural modifications of chromosomes involving a re-arrangement or loss of genes which may influence heredity by causing aberrations and certainly influence linkage and crossing-over.

In some cases, it has been found that a gene located at one position on a chromosome behaves differently when placed on a different position. This is known as the position effect. A very striking example of this is the ‘bar-eyed’ character of Drosophila.

While structural modifications of chromosome occur in nature it has been possible to get a great number of them by subjecting dividing cells to harsh treatment, chiefly by X-rays and other ionising radiations in the same way as explained for gene mutation. Structural modifications may be of several types (Fig. 874).

Deficiency:

A deficiency has a bit of a chromosome lost altogether. Some genes are, therefore lost. A deficiency may be terminal when it involves the end of a chromosome, or intercalary when it is an intermediate part that is deficient. Intercalary deficiency is also called deletion. Both terminal and intercalary deficiencies are known in maize. They may arise spontaneously or as a result of artificial radiation.

Deletions have been extensively studied in Drosophila where the salivary glands have enabled another method of location of genes.

It has been explained that in a sali­vary gland chromosome the two homologues remain in a stage of synapsis. If a mutation arises by deletion and if this mutated individual be crossed with a normal, the hybrid will be a heterozygote and in its salivary gland cells there will be the pair of chromo­somes of which one homologue is normal and the other deleted.

Close examination of the band of this chromosome shows exactly which bands are missing and, since the two homologues pair band by band, there will be a short curvature at the point of deletion since one homologue is shorter by a few bands there (Fig. 875).

By this observation, it is possible to locate the gene on the particular chromosome and by studying a number of such deleted mutants in the same way it is possible to get a sort of chromosome map as obtained by studying crossover percentages.

It is found that the two types of chromosome maps tally with each other keeping in mind that the crossover values at certain regions of the chromo­somes are known not to be exactly pro­portional to the distance. Deletion causes a disturbance in the genie balance and gametes with deleted chromosomes are often inviable. In Droso­phila, deletion of a bit containing more than 50 bands has lethal effect.

Duplication:

A broken bit of a chromosome may remain free in the nucleus as a fragment in addition to two complete homologues. However, no such fragment can sur­vive if it does not contain a centromere.

Thus, some alleles will be represented thrice. The broken bit, instead of remaining free may also remain attached to some other broken chromosome (which may or may not be its homologue) at an intercalary position. It should be remembered that there can be no attachment to the unbroken telomere end.

Translocation:

A broken bit of a chromosome may get attached to some other chromosome. Translocations are usually reciprocal—somewhat resembling crossing-over but very different from the latter as whole chromosomes are involved here. Such reciprocal translocation may involve homologous or non-homologous chromosomes.

Simple translocation of only one bit of a chromosome to another is extremely rare. If that rare event happens, the broken bit may even get re-attached in a different position on the mother chromosome.

A segment of a chromosome gets inverted during reattachment. Thus, a chromosome having the genes abcdef in linear order may get the segment cd inverted.

Then the new arrangement will be abdcef.

Fig. 874 shows that structural modi­fications cause typical appearances during pachytene pairing as the allelic genes tend to come side by side.

Inversions also are widely found. An inversion not containing a centromere (called a paracentric inversion) and followed by a crossover may cause an anaphasic inversion chromatid bridge and an acentric fragment as explained in Fig. 876.

Translocation is widely present in plants and animals—in Datura, maize, pea, wheat, Tradescantia, Rhoeo, etc. Segmental interchanges between chromosomes (trans­location) lead to ring formation (Fig. 877).

Related Articles:

• Notes on Mutation: Meaning and Historical Account
• Mutation: Definition, Detection and Types | Genetics
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• Mutation Genetic Change

Mutation - A Genetic Change

Mutation definition.

“Mutation is the change in our DNA base pair sequence due to various environmental factors such as UV light, or mistakes during DNA replication.”

Table of Contents

Classification & types of mutations, frequently asked questions, what are mutations.

The DNA sequence is specific to each organism. It can sometimes undergo changes in its base-pairs sequence. It is termed as a mutation. A mutation may lead to changes in proteins translated by the DNA. Usually, the cells can recognize any damage caused by mutation and repair it before it becomes permanent.

A mutation is a sudden, heritable modification in an organism’s traits. The term “mutant” refers to a person who exhibits these heritable alterations. Mutations usually produce recessive genes.

Causes of Mutations

The mutation leads to genetic variations among species. Positive mutations are transferred to successive generations.

E.g.  Mutation in the gene coding for haemoglobin causes sickle cell anaemia. The R.B.Cs become sickle in shape. However, in the African population, this mutation provides protection against malaria.

A mutation in the gene controlling the cell division leads to cancer.

Let us have an overview of the causes and impacts of mutation.

Also Read:  Mutagens

The mutation is caused due to the following reasons:

Internal Causes

Most of the mutations occur when the DNA fails to copy accurately. All these mutations lead to evolution. During cell division , the DNA makes a copy of its own. Sometimes, the copy of the DNA is not perfect and this slight difference from the original DNA is called a mutation.

External Causes

When the DNA is exposed to certain chemicals or radiations, it causes the DNA to break down. The ultraviolet radiations cause the thymine dimers to break resulting in a mutated DNA.

DNA Mutation

Effects of Mutation

There are several mutations that cannot be passed on to the offsprings. Such mutations occur in the somatic cells and are known as somatic mutations.

The germline mutations can be passed on to successive generations and occur in the reproductive cells.

Let us have a look at some of the effects of mutation:

Beneficial Effects of Mutation

• Few mutations result in new versions of proteins and help the organisms to adapt to changes in the environment. Such mutations lead to evolution.
• Mutations in many bacteria result in antibiotic-resistant strains of bacteria that can survive in the presence of antibiotics.
• A unique mutation found in the population of Italy protects them from atherosclerosis, where fatty materials build up in the blood vessels.

Effects of Mutations

• Genetic disorders can be caused by the mutation of one or more genes. Cystic fibrosis is one such genetic disorder caused by the mutation in one or more genes.
• Cancer is another disease caused by the mutation in genes that regulate the cell cycle.

For more information on mutation, its causes and effects, keep visiting BYJU’S website or download BYJU’S app for further reference.

Give the meaning of mutation.

Mutation means an alteration in the genes or chromosomes of a cell. This shift in the gametes may impact the development and structure of the progeny. A mutation in biology is a modification of the nucleic acid sequence of a virus, extrachromosomal DNA, or the genome of an organism. The observable traits of an organism (phenotype) may or may not change as a result of a mutation.

Define gene mutation. Give examples.

Gene or genetic mutations are modifications to the DNA sequence that take place as the cells divide and generate copies of themselves. The DNA provides instructions on how to develop and run the human body. Genetic changes may result in diseases like cancer or, in the long run, enable people to adapt to their surroundings more successfully.

Examples include animals possessing extra body parts after birth, such as four-legged ducks, cyclops kittens, and snakes with two heads. Genetic disorders in humans, like Sickle-cell disease, are frequently brought on by gene mutations or chromosomal aberrations. Angelman syndrome, Canavan disease, colour blindness, cystic fibrosis, cri-du-chat syndrome, Down syndrome, haemophilia, Klinefelter syndrome, Duchenne muscular dystrophy, phenylketonuria, Prader-Willi syndrome, Tay-Sachs disease, and Turner syndrome are additional examples of common mutations in human beings.

What is DNA mutation?

A DNA mutation is a long-lasting alteration to the nucleotide sequence of DNA that can occur during replication and recombination. Most of the time, mutations are benign unless they result in tumour growth or cell death. Base pair substitution, deletion, or insertion can all result in mutations in damaged DNA. Cells have developed processes for repairing damaged DNA owing to the deadly consequences of DNA mutations.

Base substitutions, deletions, and insertions are the three different forms of DNA mutations.

What are the causes of gene mutation?

A gene mutation is a permanent change to a DNA sequence that makes it different from the sequence found in other people. A genetic mutation occurs during cell division when the grow and divide and replicate. Mutations can impact anything from a single DNA base pair (a unit of genetic composition) to a significant portion of a chromosome that contains numerous genes.

How does mutation affect genetic change?

A population can acquire new alleles through mutations, increasing the genetic diversity of the population. For mutations to impact an organism’s offspring, they must: 1) arise in cells that give rise to the succeeding generation; and 2) alter the genetic code. Diversity among organisms is ultimately produced through the interaction of hereditary mutations and environmental stresses.

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Mechanisms of DNA damage, repair and mutagenesis

Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue.

Introduction

Preserving genomic sequence information in living organisms is important for the perpetuation of life. At the same time, mutagenesis plays an indispensible part in its maintenance and evolution, while also contributing to cancer, certain human diseases and aging. It is known that DNA, the basic unit of inheritance, is an intrinsically reactive molecule and is highly susceptible to chemical modifications by endogenous and exogenous agents. Furthermore, the DNA polymerases engaged in DNA replication and repair make mistakes, thereby burdening cells with potentially disadvantageous mutations. However, cells are equipped with intricate and sophisticated systems—DNA repair, damage tolerance, cell cycle checkpoints and cell death pathways—that collectively function to reduce the deleterious consequences of DNA damage.

Cells respond to DNA damage by instigating robust DNA damage response (DDR) pathways, which allow sufficient time for specified DNA repair pathways to physically remove the damage in a substrate-dependent manner. At least five major DNA repair pathways—base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end joining (NHEJ)—are active throughout different stages of the cell cycle, allowing the cells to repair the DNA damage. A few specific lesions can also be removed by direct chemical reversal and interstrand crosslink (ICL) repair. These repair processes are key to maintaining genetic stability in cells. In addition, certain types of DNA damage are substrates for the DNA damage tolerance pathways. In higher eukaryotes, for example, a well-orchestrated group of five main translesion synthesis (TLS) polymerases—REV1, POL ζ, POL η, POL κ and POL ι—bypass the damage to enable the continuation of replication, but with the possibility of a concurrent introduction of an incorrect base that can be fixed into a mutation in the subsequent round of replication. Under the circumstances, when the damaged DNA persists, programmed cell death or apoptosis, a regulatory response to DNA damage, is activated to get rid of cells with extensive genome instability.

Not surprisingly, in many cancers, DNA repair, DNA damage tolerance and DDR pathways are disrupted or deregulated, which increases mutagenesis and genomic instability, thereby promoting cancer progression [ Bouwman and Jonkers, 2012 ; Ghosal and Chen, 2013 ; Wolters and Schumacher, 2013 ]. Likewise, aging is attributed to attrition of chromosomal ends and failing capacities of a combination of these pathways. Other diseases, such as neurodegenerative disorders, result from a combinatorial failure of more than one of these processes. The 2015 Nobel Prize in Chemistry to Drs. Lindahl, Modrich and Sancar highlights the importance of mechanisms of DNA damage and repair and their implications for human health. In this review we will discuss the details of various types and mechanisms of DNA damage and the compensatory repair and tolerance pathways.

Types of DNA damage

DNA damage can be categorized into two main classes based on its origin: endogenous and exogenous. The majority of the endogenous DNA damage arises from the chemically active DNA engaging in hydrolytic and oxidative reactions with water and reactive oxygen species (ROS), respectively, that are naturally present within cells. Such inherently predisposed reactions of DNA with molecules from its immediate surroundings fuel the development of hereditary diseases and sporadic cancers [ Visconti and Grieco, 2009 ; Reuter et al., 2010 ; Perrone et al., 2016 ]. Exogenous DNA damage, on the other hand, occurs when environmental, physical and chemical agents damage the DNA. Examples include UV and ionizing radiation, alkylating agents, and crosslinking agents. We offer here a brief summary of the main endogenous and environmental agents that produce the different classes of DNA damage that then become substrates for the specific DNA repair pathways discussed in the subsequent section.

Endogenous DNA damage

Replication errors, dna base mismatches and topoisomerase-dna complexes.

Every time a human cell replicates, approximately 3 X 10 9 bases are copied over by high fidelity replicative polymerases (δ and ε). However, a battery of other DNA polymerases (α, β, σ, γ, λ, REV1, ζ, η, ι, κ, θ, ν, μ, Tdt and PrimPol) can carry out lower fidelity DNA synthesis during DNA replication or repair ( Table 1 ) [ Loeb and Monnat (2008) ]. High fidelity DNA synthesis is a consequence of structural and biochemical attributes of replicative DNA polymerases, which ensure the insertion of a correct complementary deoxynucleotide opposite the template base. This is accomplished, for instance, by: 1) the thermodynamic stability and base-pair energetics of the incoming dNTP and template base, 2) the geometric selection of a correctly shaped and sized dNTP in the polymerase’s active site, and 3) removing an incorrectly inserted deoxynucleotide by a 3′-5′ deoxynucleotide exonuclease. In addition, the mismatch repair (MMR) pathway contributes to replication fidelity by more than 100-fold by correcting the rare errors that have escaped proofreading by replicative polymerases [ Kunkel, 2004 ; Kunkel, 2009 ; Kunkel, 2011 ].

Shows representative human DNA polymerases. BER (base excision repair), MMR (mismatch repair), NER (nucleotide excision repair), DSBR (double strand break repair), dCTP (deoxycytidine phosphate), FA (fanconi anemia), TLS (translesion synthesis), SHM (somatin hypermutation), ICL (interstrand cross link), dRP (deoxyribosephosphate), TdT (Terminal deoxynucleotidyl transferase), RT (reverse transcriptase), AEP (archaeo-eukaryotic primases).

Nevertheless, base substitutions and single base insertion and deletion errors still accumulate at a frequency of 10 −6 to 10 −8 per cell per generation [ Kunkel, 2004 ; Kunkel, 2009 ]. Additional replication errors accumulate from strand slippage events at repetitive sequences causing insertions and deletions of nucleotides that can potentially change the reading frame [ Viguera et al., 2001 ; Chatterjee N., 2013 ]. Other times, the replicative polymerases incorrectly incorporate uracil in the DNA or end up with a compromised fidelity because of the alterations of the relative and absolute concentrations of dNTPs and rNTPs within the cell’s environment [ Andersen et al., 2005 ; Vertessy and Toth, 2009 ; Kumar et al., 2011 ; Clausen et al., 2013 ; Buckland et al., 2014 ; Potenski and Klein, 2014 ]. These incorrectly paired/incorporated nucleotides that escape proofreading and MMR become mutations in the next round of replication and are a major source of spontaneous mutagenesis.

Another source of endogenous DNA damage results from the action of topoisomerase enzymes (for example: TOP I, TOP II, TOP III; 7 TOP genes are found in the human genome), which primarily remove superhelical tension on DNA during replication and transcription [ Wang, 2002 ; Pommier et al., 2006 ]. TOP1, for example, transiently nicks the supercoiled DNA and facilitates rotation of the broken strand around the TOP1-bound DNA strand to relax the DNA. Thereafter, TOP1 religates the breaks by aligning the 5′-OH group of the DNA with the tyrosine-DNA phosphodiester bond to resolve the complex [ Stewart et al., 1998 ; Carey et al., 2003 ]. Misalignment of the 5′-OH DNA end stabilizes the cleavage complex to form a DNA lesion [ Pommier and Cherfils, 2005 ; Pommier and Marchand, 2005 ]. Interestingly, anticancer drugs such as camptothecin and many naturopathic compounds are known to stabilize the TOP1-DNA cleavage complexes [ Staker et al., 2002 ; Han et al., 2008 ]. Additionally, DNA adducts (from UV and benzene derivatives) and aberrant DNA structures (nicks, mismatches, abasic sites) can also irreversibly trap the TOP1-DNA cleavage complex into DNA lesions called suicidal complexes [ Burgin et al., 1995 ; Pourquier and Pommier, 2001 ; Meng et al., 2003 ]. TOP1-associated DNA damage is usually repaired by reversal of these complexes or is excised by TDP1 (tyrosyl DNA phosphodiesterase) and endonucleases [ Pommier et al., 2006 ].

Spontaneous base deamination

Base deamination is a major source of spontaneous mutagenesis in human cells, where cytosine (C), adenine (A), guanine (G), and 5-methyl cytosine (5mC) in DNA lose their exocyclic amine to become uracil (U), hypoxanthine, xanthine and thymine (T), respectively ( Figure 1B ). Interestingly, these base deamination events occur at a much higher frequency in single-stranded versus double-stranded DNA and are often exacerbated by transient single strandedness during active replication, transcription and recombination [ Lindahl, 1993 ; Yonekura et al., 2009 ]. In the case of deamination of cytosine, for instance, the native C:G base pairing alters to a U:A base pair in the first round of replication, which in the next round of replication results in a CG→TA mutation. Cytosine and 5-methyl cytosine are the most frequently deaminated, but 5-methyl cytosine is deaminated three to four times more frequently than cytosine [ Lindahl, 1979 ]. While deaminated cytosine is rapidly removed from DNA by uracil-DNA glycosylase, the G:T base pair resulting from deamination of 5-methylcytosine is instead a substrate for the thymine DNA glycosylase (TDG) and the relatively slow MMR process [ Lindahl, 1979 ; Wiebauer and Jiricny, 1990 ; Waters and Swann, 1998 ]. Consequently, the GC→AT transition at the CpG sequences accounts for one-third of the single site mutations responsible for hereditary diseases in humans [ Cooper and Youssoufian, 1988 ; De Bont and van Larebeke, 2004 ].

Common DNA base lesions. A) Normal structures of DNA bases: adenine (A), guanine (G), cytosine (C) and thymine (T). B) Deaminated bases: hypoxanthine, xanthine, uracil and thymine arising from deamination of exocyclic bases of adenine, guanine, cytosine and 5-methylcytosine (5-mC) respectively. C) Oxidized DNA bases: formamidopyrimidine derivative of adenine (Fapy-A), 7,8 dihydro-8-oxoguanine (8-oxo-G) and thymine glycol. D) Methylated DNA bases: N3-methyladenine, N7-methylguanine, O 6 -methylguanine, N3-methylcytosine, O 4 -methylthymine, O 4 -ethylthymine and N3-methylthymine.

Paradoxically, cytosine deamination is also a normal route for somatic hypermutagenesis during antibody development due to the action of the deaminase enzymes AID (activation-induced deaminase) and APOBEC1 (Apolipoprotein B mRNA editing enzyme catalytic polypeptide 1), which mediate host defense against reteroviruses [ Goff, 2003 ; Blanc and Davidson, 2010 ; Chandra et al., 2015 ]. In addition to the endogenous deamination sources, environmental exposure to UV radiation, intercalating agents, nitrous acid and sodium bisulfite can in general enhance base deamination rates in the DNA [ Chen and Shaw, 1993 ; Moyer et al., 1993 ; Pfeifer et al., 2005 ; d’Ischia et al., 2011 ]. From an evolutionary standpoint, cytosine deamination from endogenous and exogenous sources may serves as a source for genetic diversity [ Fryxell and Zuckerkandl, 2000 ; Nabel et al., 2012 ].

Abasic sites

Abasic or AP (apurinic/apyrimidic) sites are continuously created in the DNA when the N-glycosyl bond, which links the nitrogenous base and the sugar phosphate backbone, either hydrolyzes spontaneously or gets cleaved by a DNA glycosylase to generate an intermediate in the BER pathway. For example, AP sites are formed when uracil is removed from the DNA by uracil-DNA glycosylase [ Lindahl and Barnes, 2000 ]. In a human cell, about 10,000 abasic sites are created per day; both extreme pH conditions and high temperatures positively impact their generation [ Lindahl, 1993 ; Tropp, 2011 ]. Abasic sites are inherently unstable and readily convert into single strand breaks (SSBs) from a β-elimination reaction that targets the 3′ phosphodiester bond of the leftover deoxyribose [ Bailly and Verly, 1988 ; Waters and Walker, 2006 ; Tropp, 2011 ; Chan et al., 2013 ]. Most AP sites are effectively removed by AP endonucleases that cleave at their 5′ end and allow the BER pathway to repair them. Alternatively, AP sites can be bypassed by TLS polymerases [ Chan et al., 2013 ]. It is not known whether other exogenous stresses could also directly propel the formation of AP sites in the genome.

Oxidative DNA damage

Reactive oxygen species (ROS) are the typical byproducts of the electron transport chain (ETC) during cellular respiration in aerobic organisms, and are additionally derived from catabolic oxidases, anabolic processes and peroxisomal metabolism [ Henle and Linn, 1997 ]. At low levels, ROS species perform important cellular functions such as serving as cellular messengers in redox signaling reactions and effecting important defense responses to invading pathogens by the immune system [ Errol C. Friedberg, 2005 ; Segal, 2005 ; Malle et al., 2007 ]. However, in excess, ROS species can cause a total of approximately 100 different oxidative base lesions and 2-deoxyribose modifications [ Bjelland and Seeberg, 2003 ; Cadet et al., 2010 ; Cadet et al., 2011 ; Cadet et al., 2012 ; Ravanat et al., 2012 ; Cadet and Wagner, 2014 ]. Ordinarily, the deleterious consequences of ROS are regulated in cells by 1) restricting respiration in the mitochondrial compartment, thereby protecting other cellular components, 2) protecting DNA by complexing it with histones, and 3) quenching of surplus ROS species by the anti-oxidant enzymes superoxide dismutase, catalase, and peroxiredoxin [ Riley, 1994 ; Mates et al., 1999 ; Mates and Sanchez-Jimenez, 1999 ]. Despite this, an overabundance of ROS species is notably associated with the development of human diseases, such as cancer, Alzheimer’s disease, Parkinson’s disease, diabetes, and heart failure [ Giacco and Brownlee, 2010 ; Liou and Storz, 2010 ; Mohsenzadegan and Mirshafiey, 2012 ; Dias et al., 2013 ; Hafstad et al., 2013 ].

The most conspicuous of the ROS species are the superoxide radicals (•O 2 − ), hydrogen peroxide (H 2 O 2 ), and the hydroxyl radical (•OH) [ Tropp, 2011 ]. Amongst these ROS species, the •OH radical, produced as a byproduct of a Fenton’s reaction of H 2 O 2 with Fe 2+ , is by far the most reactive, and is capable of damaging DNA, proteins and lipids [ Imlay et al., 1988 ; Dizdaroglu et al., 1991 ]. These electrophilic •OH radicals react with DNA bases by 1) adding to their double bonds, 2) abstracting hydrogen atoms from their methyl groups, and 3) attacking the sugar residue in their immediate vicinity [ Breen and Murphy, 1995 ; Winterbourn, 2008 ]. For example, thymine glycol residues are generated from a •OH attack on the C5/C6 double bonds of thymine ( Figure 1C ). Similarly, the •OH radical produced as a byproduct of the Fenton reaction of H 2 O 2 and Fe 2+ induces an imidazole ring opening in guanine and adenine to form the fragmented purine structure formamidopyrimidine ( Figure 1C ) [ Chetsanga et al., 1981 ; Errol C. Friedberg, 2005 ; C., 2006 ]. Another biologically significant and major oxidative base lesion formed from hydroxylation of the C-8 residue of guanine is the saturated imidazole ring 7,8 dihydro-8-oxoguanine (8-oxo-G) ( Figure 1C ). 8-oxo-guanine pairs incorrectly with adenine instead of cytosine, thereby adding to the overall mutational load, and is further oxidized to other deleterious secondary DNA lesions because of its low oxidation potential [ Kasai and Nishimura, 1984 ; Cheng et al., 1992 ; Cadet et al., 1999 ; Cadet et al., 2010 ].

Other than attacking DNA bases, ROS radicals can also compromise the DNA backbone causing an estimated 2300 single strand breaks per cell per hour in mammalian cells [ Giloni et al., 1981 ; R, 1981 ; Henner et al., 1983a ; Henner et al., 1983b ]. While the BER pathway repairs the oxidized bases, the breaks in the DNA backbone are repaired by the single strand break repair (SSBR) pathways or the double strand break repair (DSBR) pathways [ Henner et al., 1983a ; Demple and Harrison, 1994 ]. Finally, lipid peroxidation, the oxidation of lipid molecules by hydroxyl radicals, generates aldehyde products such as malondialdehyde and 4-hydroxynonenal, which can react with adenine, guanine and cytosine to form mutagenic adducts [ Marnett, 2000 ; Plastaras et al., 2000 ; VanderVeen et al., 2001 ]. About 1 adduct per 10 6 – 10 7 parent DNA bases results from lipid peroxidation events and the number of mutagenic adducts are expected to be even higher for metal storage diseases such as Wilson’s disease and hemochromatosis [ Carmichael et al., 1995 ; Luczaj and Skrzydlewska, 2003 ; Broedbaek et al., 2009 ].

DNA methylation

S-adenosylmethionine (SAM), which is used as a methyl donor by methyl transferases during normal methylation reactions, can also spontaneously generate up to 4000 N7-methylguanine, 600 N3-methyladenine and 10–30 O 6 -methylguanine residues per cell per day in mammals ( Figure 1d ) [ Rydberg and Lindahl, 1982 ; Holliday and Ho, 1998 ; De Bont and van Larebeke, 2004 ]. Other methylating agents include endogenous nitrosated bile salts, betaine, choline, and environmental agents such as tobacco smoke, diet, pollution or derivatives of N-nitroso compounds [ O’Driscoll et al., 1999 ; Zhao et al., 1999 ]. O 6 -methylguanine and the related residues O 4 -methylthymine and O 4 -ethylthymine are highly mutagenic, producing G:C→A:T and T:A→C:G transition mutations, respectively. In contrast, N3-methyladenine is only partly cytotoxic due to inhibition of DNA synthesis, while the N7-methylguanine residue is essentially harmless unless it undergoes a spontaneous cleavage to generate an AP site or opens the imidazole ring to form formamidopyrimidine [ Loveless, 1969 ; Loechler et al., 1984 ; Larson et al., 1985 ; Preston et al., 1986 ; Preston et al., 1987 ; O’Connor et al., 1988 ; Singer et al., 1989 ; Tudek et al., 1992 ]. Other minor methyl lesions produced by SAM are the mutagenic N3-methylthymine and N3-methylcytosine ( Figure 1D ) [ Boiteux and Laval, 1982 ; Saffhill, 1985 ; Huff and Topal, 1987 ].

Methylated bases are removed from DNA by two main pathways: 1) direct reversal of the DNA damage by O 6 -methylguanine DNA methyltransferase or by oxidation by an α-ketoglutarate-dependent dioxygenase AlkB homolog, and 2) BER, which is initiated by DNA glycosylases to remove the methylated bases by catalyzing the cleavage of their glycosidic bonds [ Sakumi and Sekiguchi, 1990 ; Tudek et al., 1992 ; Huang et al., 1994 ; Zak et al., 1994 ; Ye et al., 1998 ]. In addition, the O 6 -methylguanine DNA lesion interestingly triggers a cytotoxic and futile cycle of MMR, by means of its abnormal base pairing with other residues [ Branch et al., 1993 ; Kat et al., 1993 ]. If left unrepaired, methylated DNA bases are a major source of spontaneous DNA damage. Alkylated DNA damage from exogenous compounds will be discussed later in the article.

Exogenous DNA damage

Ionizing radiation (ir).

Ionizing radiation, composed of alpha, beta, gamma, neutrons and X-rays, is abundant in our environment, being produced from diverse sources ranging from rocks, soil, and radon, to cosmic radiation and medical devices. Each type of radiation can be classified to describe its effect (direct or indirect) and ionization density (linear energy transfer (LET)). Depending on the amount of energy transferred to matter, radiations are classified as either high LET (alpha rays) or low LET (beta and gamma). Cumulatively, IR can damage the DNA either directly, or by indirect means, such as by radiolysis of the surrounding water to generate a cluster of highly reactive hydroxyl radicals (•OH) [ Errol C. Friedberg, 2005 ; Omar Desoukya, 2015 ]. The presence of oxygen and other reactive species in the surrounding also potentiates the formation of other DNA-reactive free radicals by IR [ Wardman, 2009 ]. In fact, indirect DNA damage from (•OH) radicals accounts to about 65% of the radiation-induced DNA damage [ Vignard et al., 2013 ]. Because of this, IR produces a spectrum of base lesions that is similar to that generated by ROS species (see previous section). Major lesions include 8-oxo-guanaine, thymine glycol and formamidopyrimidines ( Figure 1C ).

Apart from causing base lesions, ionizing radiation also causes single strand breaks with a unique signature, where the DNA breaks have 3′ phosphate or 3′-phosphoglycolate ends rather than 3′-OH ends. In addition, fragmented sugar derivatives and loss of terminal base residues culminate into clustered damage or single stranded gaps [ Henner et al., 1982 ; Henner et al., 1983b ; Obe et al., 1992 ]. AP endonucleases, polynucleotide kinase/phosphatase (PNKP) and tyrosyl DNA phosphodiesterase 1 (TDP1) can efficiently process the modified ends and enable repair of the IR-induced single strand beaks [ Price, 1993 ; Jilani et al., 1999 ; Zhou et al., 2005 ; El-Khamisy et al., 2007 ]. A particularly important radiation-induced lesion is the double strand break, formed from multiple damaged sites closely positioned on both DNA strands [ Hutchinson, 1985 ; Iliakis, 1991 ]. Although toxic, IR-induced double strand breaks can be repaired by the HR pathway [ Lomax et al., 2013 ].

Ultraviolet (UV) radiation

UV radiation emanating from the sun is the leading cause of skin cancers in humans [ Davies, 1995 ; KIEFER, 2007 ]. Typically, UV radiation is categorized into three classes based on the range of wavelength: UV-C (190–290 nm), UV-B (290–320 nm) and UV-A (320–400nm). DNA absorbs maximal UV radiation at 260 nm, beyond which the photo-absorption drops dramatically. Sunlight is composed of 5.1% UV-A, 0.3% UV-B, 62.7% visible light and 31.9% infrared, as the hazardous UV-C is mostly filtered out by the ozone layer [ Davies, 1995 ]. The effects of UV on matter are disseminated in two ways. First, if the UV is absorbable, molecules in matter are excited leading to their photochemical alteration. Second, if UV cannot be directly absorbed, energy transfer from nearby molecules called photosensitizers indirectly affects matter. UV damage DNA by both pathways.

Laboratory studies have shown that UV-C damages DNA primarily by causing covalent linkages between two adjacent pyrimidines. Here the two major photoproducts are the cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6 – 4) pyrimidone photoproducts ((6 – 4) PPs) ( Figure 2 ). Their relative formation frequency depends on wavelength and dose of light [ Varghese, 1972 ; Mitchell and Nairn, 1989 ; Davies, 1995 ], although, the yield of (6 – 4) PP is slightly less than CPDs [ Mitchell and Nairn, 1989 ]. Other minor photoproducts are also generated, such as pyrimidine hydrate, thymine glycols, and dipurine adducts [ Demple and Linn, 1982 ; Bose et al., 1983 ; Kumar et al., 1991 ; Mitchell et al., 1991 ]. In CPDs, a cyclobutane ring covalently links the two adjacent pyrimidines, whereas in (6 – 4) PP, the C6 position of one pyrimidine is covalently linked to C4 position of the adjacent pyrimidine. These bulky dimers distort the helix, requiring TLS polymerases for replication past them, thereby contributing to mutagenicity. For example, C:G→T:A, T:A→C:G and characteristic tandem CC→TT transition mutations result from pyrimidine dimers [ Chan et al., 1985 ; Dumaz et al., 1993 ; Gentil et al., 1996 ; Naegeli, 1997 ]. An interesting attribute of the (6 – 4) PP is that it undergoes photoisomerization to a Dewar valence isomer in the presence of UV-B, while reverting to the conventional (6 – 4) PP structure when exposed to UV-C light [ Mitchell and Nairn, 1989 ; Davies, 1995 ]. If these lesions are left unrepaired or are not bypassed, they result in cytotoxicity.

Main UV radiation-induced DNA base lesions. A) Representative cyclobutane pyrimidine dimers (CPD). Shown here are cyclobutane thymine dimers. B) Representative pyrimidine (6 – 4) pyrimidone photoproduct [(6 – 4)PP]. Shown here are derivatives of two thymine bases linked via C6 of one thymine base and C4 of the other thymine base.

UV-C is widely used in laboratory investigations because of its maximal absorption by DNA, producing more photoproducts than the UV-A and UV-B radiations, which are also physiologically relevant UV wavelengths that also cause DNA damage [ KIEFER, 2007 ]. UV-B for instance causes the formation of pyrimidine dimers, but does so less efficiently than UV-C [ You et al., 2000 ; Errol C. Friedberg, 2005 ; Rastogi et al., 2010 ]. UV-A damages DNA by inducing DNA adduct formation by photooxidation reactions and by the excitation of endogenous (porphyrins and flavins) and exogenous (psoralens, tetracycline, promazine and methylene blue) photosensitizers [ Epe, 1991 ; Kvam and Tyrrell, 1997 ; Douki et al., 1999 ]. In addition, UV-A-mediated photosensitization can induce 8-oxoG formation or an excess accumulation of cyclobutane dimers [ Epe, 1991 ; Rochette et al., 2003 ]. In mammalian cells, near and far UV radiations are known to cause DNA protein crosslinks, while UV-A radiation results in DNA strand breakages [ Peak and Peak, 1986 ; Errol C. Friedberg, 2005 ]. UV lesions are repaired by direct reversal of UV-damaged bases, NER, interstrand crosslink (ICL) repair, translesion synthesis, or homologous recombinations (HR), all of which either repair the lesions or enable cells to tolerate their presence [ Sancar, 1996 ; Errol C. Friedberg, 2005 ; Waters and Walker, 2006 ; Eppink et al., 2011 ].

Exogenous chemical agents

Alkylating agents.

Exogenous alkylating agents are primarily produced from dietary components, tobacco smoke, biomass burning, industrial processing and chemotherapeutic agents [ Lawley, 1966 ; AE, 1990 ; Crutzen and Andreae, 1990 ]. The electrophilic alkylating agents react with increased affinity to the highly nucleophilic base ring nitrogens, especially the N7 of guanine and N3 of adenine, and slightly less so with the oxygens. Examples of adducted DNA bases include modified adenine (at N1, N3, N 6 and N7), guanine (N1, N 2 , N3, N7 and O 6 ), cytosine (N3, N 4 and O 2 ), thymine (N3, O 2 and O 4 ), and alkyl phosphates in the DNA backbone (exocyclic positions on DNA bases are in italicized superscripts) [ Singer and Kusmierek, 1982 ; Singer, 1986 ; Errol C. Friedberg, 2005 ]. Mechanistically, alkylating agents add the alkyl group by either 1) an S N 1 substitution reaction that progresses via the first order kinetics and involves a carbonium ion intermediate, or, 2) an S N 2 substitution reaction that follows the second order kinetics, and in general produces adducts that are less mutagenic and carcinogenic than those of the S N 1 pathway [ Naegeli, 1997 ], although evidence has been presented that some S N 1 alkylating agents may not proceed via the carbonium ion intermediate [ Loechler, 1994 ].

Most common alkylating agents that are regularly used in labs, including methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), N-methyl -N′ –nitro-N-nitrosoguanidine (MNNG) and methylnitrosourea (MNU) ( Figure 3A ), react with DNA to generate mutagenic and carcinogenic lesions. For example, MMS produces the mutagenic N7-methylguanine and N3-methyladenine, both of which are susceptible to cleavage of the N-glycosidic bond, thereby generating AP sites, while MNNG and MNU produce O 6 -methylguanine, which mispairs with T and induces G:C→A:T mutations [ Loechler et al., 1984 ; Beranek, 1990 ; Wyatt and Pittman, 2006 ].

Structures of representative DNA damaging agents. A) Alkylating agents: methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), N-methyl -N′ –nitro-N-nitrosoguanidine (MNNG) and methylnitrosourea (MNU). B) Crosslinking agents: Cyclophosphamide, cisplatin and psoralen. C) Aromatic amines: 2-aminofluorene (AF) and N-acetyl-2-aminofluorene (AAF). D) Polycyclic aromatic hydrocarbons: benzo( a )pyrene and dibenzo[ a,l ]pyrene. E) Reactive electrophiles: 4-nitroquinoline 1-oxide (4-NQO). F) Toxins: Afaltoxin B1.

Other classical examples of alkylating agents are sulfur and the nitrogen mustards, first used in World War I, and in many other conflicts since including the present day Syria. The mustards drive S N 1 reactions, and are bifunctional in that they carry two reactive groups, instead of one as in monofunctional alkylating agents, and thus have the potential to react with two different sites on the DNA. Such bifunctional reactions result in intra- and interstrand crosslinks, along with the DNA-protein crosslinks, which block DNA metabolic activity [ Lawley, 1966 ; AE, 1990 ]. These properties of the mustards have been exploited in their use as chemotherapeutic alkylating agents [ DeVita and Chu, 2008 ]. One clinically relevant alkylating agent for chemotherapy is cyclophosphamide ( Figure 3B ) used in the treatment of lymphomas, leukemias and solid tumors [ Emadi et al., 2009 ]. Another class of crosslinking agents that are used in chemotherapy includes cisplatin ( Figure 3B ), the first FDA approved platinum compound that is used to treat a wide variety of cancers [ Kelland, 2007 ; Dasari and Tchounwou, 2014 ]. A crosslinking agent that is not an alkylating agent, psoralen (a furocoumarin) ( Figure 3B ), intercalates into DNA and cause both interstrand crosslinks and pyrimidine adducts upon photoactivation by UV-A [ Yurkow and Laskin, 1991 ]. The combined psoralen+UV-A or PUVA has been effectively used for treating skin conditions such as psoriasis, eczema and cutaneous T-cell lymphomas. Direct damage reversal, BER and ICL repair are the putative repair pathways that respond to alkylated base damage [ Wyatt and Pittman, 2006 ].

Aromatic amines

Aromatic amines are principally produced from cigarette smoke, fuel, coal, industrial dyes, pesticides and everyday high temperature cooking [ Sugimura, 1986 ; Skipper et al., 2010 ]. Upon activation by the P450 monooxygenase system, aromatic amines are converted into the carcinogenic (ester and sulfate) alkylating agents that attack the C8 position of guanine [ Hammons et al., 1997 ; Naegeli, 1997 ]. The most intensively studied examples of aromatic amines are 2-aminofluorene (AF) and its acetylated derivative N-acetyl-2-aminofluorene (AAF) ( Figure 3C ), which were originally used as insecticides until they were recalled due to their carcinogenic properties [ Kriek, 1992 ]. C8-guanine lesions formed from aminofluorenes are known to form persistent lesions that ultimately give rise to base substitutions and frameshift mutations [ Mah et al., 1989 ; Heflich and Neft, 1994 ; Shibutani et al., 2001 ]. The mutagenic properties of the C8-guanine lesion come from its characteristic ability to adopt two conformations while on the DNA [ Eckel and Krugh, 1994a ]. In the external conformation where the fluorene moiety protrudes out, there is minimal disturbance to Watson-Crick base pairing, which allows these isomers to be effectively bypassed by TLS polymerases [ Vooradi and Romano, 2009 ]. While in internal conformation, the C8-guanine lesion and its partner cytosine are displaced into the minor groove, completely altering the geometry and acting as a very mutagenic substrate on the DNA [ Kriek, 1992 ; Eckel and Krugh, 1994a ; Eckel and Krugh, 1994b ]. The NER pathway is known to repair C8-guanine adducts in human cells [ Mu et al., 2012 ]

Polycyclic aromatic hydrocarbon (PAH)

Polycyclic aromatic hydrocarbons are carbon compounds with two or more aromatic rings and are generally known to be inert, nonpolar and widely distributed carcinogens in the environment [ Harvey, 1991 ]. Common sources include tobacco smoke, automobile exhaust, charred food and incomplete combustion of organic matter and fossil fuels [ Schoket, 1999 ; Yu, 2002 ]. The carcinogenicity of these compounds was first documented in 1775, followed by their isolation from coal tar and the later elucidation of their mechanism of action [ Butlin, 1892 ; Phillips, 1983 ; Fujiki, 2014 ]. PAHs depend on the P-450 system of the liver to generate reactive intermediates that react with DNA [ Phillips, 1983 ]. Photo-oxidation, one electron oxidation, multiple ring-oxidation and nitrogen-reduction pathways are also known to activate the PAHs [ Strniste et al., 1980 ; Fu, 1990 ; RamaKrishna et al., 1992 ; Rogan et al., 1993 ; Flowers et al., 1997 ; Penning et al., 1999 ; Yu, 2002 ].

Prominent examples of PAHs are naphthalene, anthracene, pyrene, 1-hydroxypyrene, 1-nitropyrene, benzo( a )pyrene and dibenzo[ a,l ]pyrene. Of these, the most well studied is benzo( a )pyrene ( Figure 3D ). Upon P-450 activation, benzo( a )pyrene generates the ultimate carcinogen (+)- anti -BPDE [(+)- 7,8-hydroxy-9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo(α)pyrene], along with the (+)-anti-BPDE and the (−)-anti-BPDE intermediates. These intermediates first intercalate into DNA, then the C10 position of the BPDE binds to the N 2 exocyclic position of guanine to form DNA adducts [ Geacintov, 1986 ; Graslund and Jernstrom, 1989 ; Cosman et al., 1992 ]. In terms of carcinogenicity, dibenzo[ a,l ]pyrene ( Figure 3D ) is the most potent PAH and poses a major cancer risk to humans [ Luch, 2009 ]. Normally, the excision repair pathways such as NER and BER repair the PAH DNA lesions if they are not bypassed by TLS polymerases [ Braithwaite et al., 1998 ; Jha et al., 2016 ].

Other reactive electrophiles

Given the space constraint and scope of this manuscript, we will only briefly touch upon a few other relevant reactive electrophiles that damage the DNA. N-nitrosamines, which are potent carcinogens, are byproducts of tobacco smoke and are also encountered by humans in preserved meats. N-nitrosamines have been implicated in the development of esophagus, stomach and nasopharynx cancers [ Bartsch and Montesano, 1984 ; Tricker and Preussmann, 1991 ; Hecht, 1999 ; Herrmann et al., 2015 ]. Another reactive electrophile, 4-nitroquinoline 1-oxide, has both carcinogenic and mutagenic properties ( Figure 3E ). Upon its metabolic activation to 4-acetoxyaminoquinoline 1-oxide (Ac-4HAQO), 4NQO1 forms covalent adducts with C8 or N 2 of guanine and N 6 of adenine, as well as causing oxidative stress that results in 8-hydroxyguanine lesion, all of which significantly adds to the strand breakage events and oral carcinogenesis [ Galiegue-Zouitina et al., 1985 ; Galiegue-Zouitina et al., 1986 ; Kohda et al., 1986 ; Hawkins et al., 1994 ; Kanojia and Vaidya, 2006 ].

Our final notable compound is the hormone estrogen, frequently used in hormonal replacement therapy, which poses a cumulative increased cancer risk after its prolonged use [ Cavalieri et al., 2000 ; Yager and Davidson, 2006 ]. Epidemiological and clinical trial studies indicate an increased breast cancer risk and other health issues from a combinatorial use of estrogen and progesterone compared to estrogen alone [ Yager and Davidson, 2006 ]. The P-450 1BI enzyme complex, constitutively expressed in breast and other tissues, hydroxylates estrogen at position 4 to produce reactive catechol estrogens, which are either oxidized to semiquinones and quinones that react with N3 and N7 position of purines, or generate ROS species [ Nutter et al., 1991 ; Nutter et al., 1994 ; Errol C. Friedberg, 2005 ]. Both of these unstable bulky adducts and oxidants produce AP sites and strand breakages [ Errol C. Friedberg, 2005 ]. Estrogen is also implicated in the development of prostate cancer, where strand breaks and lipid peroxidation were the phenotypic readouts in a prostate rat model [ Ho and Roy, 1994 ; Nelles et al., 2011 ].

Natural toxins constitute a class of genotoxic and carcinogenic compounds, which are normally used by microorganisms or fungi in defense responses [ Ames et al., 1990 ]. Human and animal exposures result from contaminated cereals, oilseeds, spices, tree nuts, milk and milk products [ Lopez et al., 2002 ]. Aflatoxins are naturally occurring toxins from Aspergillus flavus and Aspergillus parasiticus, of which aflatoxin B1 is the most potent liver carcinogen [ Bennett and Klich, 2003 ]. After passively diffusing into cells, aflatoxin B1 ( Figure 3F ) is metabolized by the P-450 complex into the active form, aflatoxin B1-8,9-epoxide. This reactive electrophile then adducts with N7 of guanine to form a positively charged product, 8,9-dihydro-8-(N7-guanyl)-9-hydroaflatoxin B1, which weakens the glycosidic bond resulting in depurination [ Essigmann et al., 1977 ; Smela et al., 2001 ].

Environmental stresses

Environmental sources of stress such as extreme heat or cold, hypoxia, and oxidative stress have been shown to cause DNA damage in human cells [ Gregory and Milner, 1994 ; Gafter-Gvili et al., 2013 ; Luoto et al., 2013 ; Neutelings et al., 2013 ; Kantidze et al., 2016 ]. These stresses have also been shown to cause mutagenesis at trinucleotide repeats, which are implicated in the development of neurodegenerative disorders via the alt-NHEJ DNA repair pathway [ Chatterjee et al., 2015 ; Chatterjee et al., 2016b ]. Equally compelling is the observation that the pathway of environmental stress-induced mutagenesis is akin to the physiological genome instability program operational in many cancer cells [ Chatterjee et al., 2015 ; Chatterjee et al., 2016b ]. It is of interest to know whether similar environmental stress-induced phenotypes can be recapitulated in mouse studies.

Other everyday use biological products have increasingly been associated with DNA damage. For example, butyl paraben (BP) and bisphenol A (BPA), found in cosmetics, pharmaceuticals, food-products and beverage processing, are linked to DNA damage in sperm cells [ Oishi, 2002 ; Meeker et al., 2010a ; Meeker et al., 2010b ; Meeker et al., 2011 ]. Food preservatives [(sodium benzoate (SB), potassium benzoate (PB) and potassium sorbate (PS)] and food additives [(citric acid (CA), phosphoric acid (PA), brilliant blue (BB) and sunset yellow (SY)] are all known to cause DNA damage [ Mamur et al., 2010 ; Zengin et al., 2011 ; Yilmaz et al., 2014 ; Pandir, 2016 ]. Additionally, plant protection products (PPPs) regularly used by orchard workers have also been associated with DNA damage [ Kasiotis et al., 2012 ]. Such instances stress the importance of global regulatory requirements on the use of chemicals that risk human health, as there may be yet unknown chemicals that have health risks.

DNA damage response (DDR)

After the DNA is damaged, lesion-specific sensor proteins initiate a DNA damage response. The DDR is a collection of mechanisms that sense DNA damage, signal its presence and promote subsequent repair [ Harper and Elledge, 2007 ]. Recruitment of DDR factors is a spatiotemporally regulated process, in which the DDR factors are assembled at the site of damage in a sequential and coordinated manner, as verified by time-lapse microscopy of discrete foci [ Harper and Elledge, 2007 ; Ciccia and Elledge, 2010 ; Polo and Jackson, 2011 ]. In addition, chromatin remodeling is an important modulator of DDR response, whereby key post-translational modifications allow assembly of specific DDR and repair factors [ Bekker-Jensen et al., 2006 ; Harper and Elledge, 2007 ; Misteli and Soutoglou, 2009 ; Polo and Jackson, 2011 ; Altmeyer and Lukas, 2013a ; Altmeyer and Lukas, 2013b ; House et al., 2014 ]. Mutations affecting DDR network components are the cause of several cancer predisposition syndromes, reflecting their overall importance in avoiding DNA damage-induced human diseases [ Ciccia and Elledge, 2010 ]. However, DNA repair pathways ( Figure 4 ) effectively remove most DNA lesions, which could otherwise result in the formation of mutations or block metabolic processes such as replication and transcription thereby causing senescence and cell death as we discuss below. Readers are directed to excellent reviews on the role of histone modifications during the DNA damage response [ van Attikum and Gasser, 2005 ; Altaf et al., 2007 ; Zhu and Wani, 2010 ].

Schematic of various DNA damage-induced DNA repair pathways. A variety of DNA damaging agents can induce DNA damage, which becomes substrate for specific DNA repair pathways. Upper panel shows representative DNA damaging agents: errors from replication, spontaneous base deamination, alkylating agents, toxins, oxidative agents, ionizing radiation, UV radiation, crosslinking agents, aromatic compounds and environmental agents such as heat, cold and hypoxia. Middle panel represents different kinds of damaged DNA: base mismatches (C:T), uracil from deamination of cytosine, an abasic site from the loss of a base from one DNA strand, methylated guanine, methylated adenine, 8-oxo-G lesion, thymine glycols, single strand breaks, double strand breaks, intrastrand cyclobutane thymine dimers and interstrand guanine crosslinks. The lower panel lists the specific DNA repair pathways that are instigated to repair DNA damages: mismatch repair corrects replication errors and other base mismatches; base excision repair removes base adducts, uracil, abasic sites and oxidative lesions; single strand break repair pathways repairs single stranded breaks in the DNA backbone; double strand break repair pathway repair double strand breaks; nucleotide excision repair removes bulky lesions and intrastrand crosslinks; interstrand crosslink repair removes interstrand linkages and translesion synthesis bypasses intrastrand crosslinks and bulky lesions.

Repair of base DNA damage

Reversal of dna damage.

Small subsets of DNA lesions—UV photolesions and alkylated bases—are simply reversed in an error-free manner. Readers are directed to excellent literature sources on the photolyase-mediated photoreactivation of UV lesions found in lower organisms and marsupials [ Kato et al., 1994 ; Errol C. Friedberg, 2005 ; Yi and He, 2013 ]. Here we will briefly discuss the reversal of alkylated DNA damage.

Two different classes of enzymes reverse alkylated bases in humans and mammals. First, the O 6 - alkylguanine-DNA alkyltransferase (AGT/MGMT) enzyme reverses O-alkylated DNA lesions, such as the O 6 -methyl, ethyl, 2-chloroethyl, benzyl and aliphatic groups, the pyridyloxobutyl adducts of guanine, and even repair the O 6 –G-alkyl- O 6 - G interstrand cross-links [ Tubbs et al., 2007 ; Fang et al., 2008 ; Pegg, 2011 ]. A single AGT molecule removes the alkylation adduct in a one step reaction by transferring the alkyl group from the oxygen of the DNA base to the cysteine residue in its catalytic pocket [ Kaina et al., 2007 ]. AGT has a special and complex significance in the cancer field. On one hand, AGT’s potential to target a diverse set of substrates is exploited to synthesize pseudosubstrates that can be used in combination with therapeutic alkylating agents to circumvent resistance to cancer chemotherapy [ Tubbs et al., 2007 ]. On the other hand, lack of AGT expression is associated with certain group of cancers [ Lee et al., 2011 ; Mokarram et al., 2013 ]. In addition, alkyltransferase-like proteins (ATLs), a family of AGT homologs, inhibit the AGT enzyme by directing the repair of bulky alkyl damage to the NER pathway [ Margison et al., 2007 ; Tubbs et al., 2009 ].

The second class of direct reversal enzymes, the AlkB-related α-ketoglutarate-dependent dioxygenases (AlkB), reverse N-alkylated base adducts. There are 9 human homologs of E. coli AlkB, which are designated as ALKBH1-8 (Alkylation Repair Homologs) and FTO (Fat Mass and Obesity associated) in human cells [ Kurowski et al., 2003 ; Gerken et al., 2007 ; Sanchez-Pulido and Andrade-Navarro, 2007 ; Yi and He, 2013 ]. For demethylation, the AlkB family proteins hydroxylate the alkyl group in a α-ketoglutarate and iron(II) dependent manner. The oxidized alkyl group is released as formaldehyde, leaving behind the original base [ Drablos et al., 2004 ; Falnes et al., 2007 ].

Base excision repair (BER)

BER corrects those forms of oxidative, deamination, alkylation and abasic single base damage that are not perceived as significant distortions to the DNA helix. In the nucleus, this repair process is mainly active in the G1 phase of the cell cycle [ Dianov and Hubscher, 2013 ]. For BER transactions, chromatin remodeling at the DNA damage site is followed by lesion recognition by a DNA glycosylase [ Odell et al., 2013 ]. At least 11 different DNA glycosylases can recognize and excise a damaged base from undistorted helices, as well as ones flipped out from the major groove [ Huffman et al., 2005 ; Krokan and Bjoras, 2013 ]. In terms of function, DNA glycosylases are either monofunctional, with only a glycosylase activity, such as the uracil glycosylases, N-methylpurine DNA Glycosylase (MPG), and MutY Homolog (MUTYH), or are bifunctional with a glycosylase and an additional β-lyase activity. Examples of the latter include the Nth-like DNA glycosylase 1 (NTHL1), Nei-like DNA glycosylase 1 (NEIL1) and Nei-like DNA glycosylase 2 (NEIL2) [ Jacobs and Schar, 2012 ]. It should be noted that 8-oxoguanine DNA glycosylase (OGG1) and NEIL3 function as both mono- and bifunctional glycosylases [ Svilar et al., 2011 ]. An abasic site created from the monofunctional glycosylases gets committed to the short-patch-repair pathway, while the bifunctional glycosylases initiate the long-patch repair pathway of BER [ Dianov and Hubscher, 2013 ].

In short patch repair, the abasic site is the substrate for the AP endonuclease (APE1 in human cells), which cleaves the phosphodiester bond 5′ to the abasic site and generates a hydroxyl residue at the 3′-end while leaving a deoxyribose phosphate (dRP) at the 5′-end. This repair gap is tailored by the 5′-dRP lyase activity of POL β (gap tailoring), followed by filling the single nucleotide gap by POL β and ligation by either LIG1 (DNA ligase 1) or a complex of LIG3 (DNA ligase 3) and XRCC1 (X-ray repair cross-complementing protein 1) [ Almeida and Sobol, 2007 ]. In long patch repair, the repair gap left behind from the bifunctional glycosylase is tailored by the 3′ phosphodiesterase activity of APE1. Thereafter, POL β (in non-proliferating cells) or POL δ/ε (in proliferating cells) synthesize in a strand-displacement manner, which is then followed by flap removal by the flap endonuclease and a LIG1-mediated ligation [ Akbari et al., 2009 ; Svilar et al., 2011 ].

While BER of 8-oxo-G lesions at CAG repeats is implicated in triplet repeat instability, downregulation of OGG1 is associated with aging, neurodegenerative disorders and cancer [ Kovtun et al., 2007 ; Tian et al., 2009 ; Curtin, 2012 ; Mollersen et al., 2012 ; Chatterjee N., 2013 ; Krokan and Bjoras, 2013 ; Chatterjee et al., 2015 ]. Specifically, mutations in POL β are found in solid cancers and POL β variants can act as dominant negative and sequence specific mutators [ Wang et al., 1992 ; Starcevic et al., 2004 ; Lang et al., 2007 ; Murphy et al., 2012 ]. In addition, PARP1 (Poly [ADP-ribose] polymerase 1) has also been shown to be required for the repair of single strand breaks and damaged purine bases by a sub-pathway of BER [ Krokan and Bjoras, 2013 ; Reynolds et al., 2015 ]. Finally, mitochondria are also known to carry out both short and long patch BER, where the synthesis step is carried out by POL γ; all of which adds to the significance of this repair pathway in the maintenance of global genome stability [ Akbari et al., 2008 ; Liu and Demple, 2010 ]. Readers are directed to these reviews for an overview of mitochondrial BER [ Bauer et al., 2015 ; Prakash and Doublie, 2015 ].

Repair of multiple and bulky base damage

Nucleotide excision repair (ner).

Nucleotide excision repair is the pathway of choice to remove bulky lesions such as CPDs and (6 – 4)PP from UV radiation, benzo[ a ]pyrene adducts, or damage from chemotherapeutic agents. NER deficiency results in a number of different human syndromes: Xeroderma Pigmentosum (XP), which is associated with a predisposition to skin cancers; Cockayne Syndrome (CS); rare UV-Sensitive Syndrome (UV S S); and Cerebro-Oculo-Facio-Skeletal syndrome (COFS) [ Errol C. Friedberg, 2005 ; Vermeulen and Fousteri, 2013 ]. However, like the BER pathway, NER contributes to the instability mechanisms in triplet repeat disorders [ Lin et al., 2006 ; Hubert et al., 2011 ; Dion, 2014 ]. To begin NER, chromatin remodeling mediated both by chromatin and NER components makes way for the NER machinery on the specified DNA lesions [ Scharer, 2013 ]. There are two major branches of NER: global genome NER (GG−NER) and transcription−coupled NER (TC−NER).

In GG-NER, the main DNA damage sensor is the XPC (Xeroderma Pigmentosum, complementation group C) protein, complexed with RAD23B (UV excision repair protein Radiation sensitive 23B) protein and CETN2 (Centrin 2). This complex scans for the presence of transient single−stranded DNA (ssDNA) caused by disrupted base pairing due to the lesion [ Masutani et al., 1994 ; Nishi et al., 2005 ]. For repair of UV-induced CPDs, the ultraviolet-damaged DNA damage−binding protein (UV–DDB) complex, consisting of DDB1 (XPE−binding factor) and the GG−NER−specific protein DDB2, directly binds to UV−radiation−induced lesions and then stimulates the binding of XPC [ Chu and Chang, 1988 ; Wakasugi et al., 2002 ; Scrima et al., 2008 ]. XPC bound to the lesion becomes the substrate for the transcription initiation factor II H (TFIIH) complex, a transcription initiation and repair factor composed of ten protein subunits that can switch functions in both transcription initiation and in NER [ Yokoi et al., 2000 ; Volker et al., 2001 ; Compe and Egly, 2012 ]. The final step of dual excision and gap filling is coordinated to prevent the ssDNA gap formation that can potentially trigger DDR signaling [ Marini et al., 2006 ; Marti et al., 2006 ; Mocquet et al., 2008 ].

The incision step of GG-NER commits the assemblage of all the proteins to NER. It involves the use of structure specific endonucleases XPF–ERCC1 and XPG (also known as ERCC5 ), which cuts the damaged strand short distances away from the 5′ and 3′ end of the lesion respectively [ Fagbemi et al., 2011 ]. The replication proteins PCNA (proliferating cell nuclear antigen), RFC (replication factor C), POL δ, POL ε or POL κ, and LIG1 or XRCC1–LIG3 carry out the final step of gap−filling synthesis and ligation. Proliferative status of the cell determines the choice of polymerase used. For example, POL ε−dependent repair predominates in non−replicating cells, while POL δ and POL κ are the main NER polymerases in replicating cells. LIG1-dependent ligation occurs in replicating cells. However, XRCC1–LIG3 complex seals the gap in non-proliferating cells because of low expression of dNTPs and LIG1 in these cells, [ Moser et al., 2007 ; Ogi et al., 2010 ].

The second NER pathway, TC-NER, is initiated by a lesion-stalled RNA polymerase II, which begins with the recruitment of TC−NER−specific proteins CSA (Cockayne syndrome WD repeat protein A; also known as ERCC8) and CSB (Cockayne syndrome protein B; also known as ERCC6), which are essential for additional assembly of other TC−NER components [ Fousteri et al., 2006 ]. These include the core NER factors (except for the GG−NER− specific UV–DDB and XPC complexes) and TC−NER−specific proteins, such as UVSSA (UV−stimulated scaffold protein A), USP7 (ubiquitin−specific−processing protease 7; also known as ubiquitin C−terminal hydrolase 7), XAB2 (XPA−binding protein 2; also known as pre−mRNA−splicing factor SYF1) and HMGN1 (high mobility group nucleosome−binding domain−containing protein 1; also known as non−histone chromosomal protein HMG14) [ Fousteri et al., 2006 ; Schwertman et al., 2012 ]. Once localized at the lesion site, the CSA-CSB complex backtracks (or reverse translocates) RNA polymerase II, exposing the lesion site. TFIIH is recruited to the lesion. The subsequent sequence of events is predicted to be the same as in GG-NER as the lesion is removed from the transcribed strand [ Marteijn et al., 2014 ].

Mismatch repair (MMR)

MMR is an evolutionarily conserved, post replicative repair pathway that contributes to replication fidelity by at least 100-fold [ Kunkel, 2009 ; Arana and Kunkel, 2010 ]. Typical substrates for the MMR pathway are base mismatches that have arisen during replication and the insertion-deletion loops (IDLs) within repetitive DNA sequences that have resulted from strand slippage events [ Errol C. Friedberg, 2005 ; Jiricny, 2006 ]. MMR is also implicated in a variety of cellular processes including microsatellite stability, meiotic and mitotic recombination, DNA-damage signaling, apoptosis, class-switch recombination, somatic hypermutation and triplet-repeat expansion [ Jiricny, 2006 ; Jiricny, 2013 ; Chatterjee et al., 2016a ]. Germline mutations in the MMR genes result in Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), which presents as a familial susceptibility to colon and ovarian cancers as well to a number of other cancers [ Peltomaki, 2001 ]. Chromatin modifications have recently been shown to pave the way for the MMR proteins to gain access to the DNA lesion and initiate repair [ Li et al., 2013 ; Li, 2014 ].

Of the eight known MSH (MutS homolog) polypeptides in eukaryotes, humans employ the MutSα heterodimer (MSH2/MSH6) to recognize base mismatches and one-to-two nucleotide IDLs, and the MutSβ heterodimer (MSH2/MSH3) to recognize large IDLs [ Kunkel and Erie, 2005 ; Sachadyn, 2010 ]. The previously accepted model was that after the lesion recognition step, the MutS complex translocates along the DNA in an ATP-dependent manner to make way for the downstream MMR components [ Jiricny, 2013 ]. Recently, the Modrich lab has shown that MutL can trap MutS at the mismatch before it forms a sliding clamp [ Qiu et al., 2015 ]. Next, the MutL complexes are recruited on to DNA and among the 4 known human MutL homologs; the MutLα heterodimer (MLH1/PMS2 heterodimer) plays a major role in MMR [ Nicolaides et al., 1994 ; Papadopoulos et al., 1994 ; Li and Modrich, 1995 ; Lipkin et al., 2000 ]. MutLα regulates termination of mismatch-provoked excision, and its endonuclease activity plays a role in the 3′ nick-directed digestion by EXO1 (Exonuclease 1) in a PCNA/RFC dependent manner [ Zhang et al., 2005 ; Kadyrov et al., 2006 ]. EXO1 also carries out the 5′ directed mismatch excision creating a gap that is stabilized by RPA [ Genschel and Modrich, 2003 ; Zhang et al., 2005 ]. POL δ, RFC, HMGB1 (high mobility group box 1 protein) and LIG1 orchestrate the final steps of new DNA synthesis and ligation [ Genschel and Modrich, 2003 ; Yuan et al., 2004 ; Guo et al., 2006 ]. PCNA plays an important role in both the initiation step of MMR and in the subsequent DNA synthesis by interacting and localizing MutSα/β and MutLα complexes at the lesion site [ Umar et al., 1996 ; Lau and Kolodner, 2003 ; Jiricny, 2006 ].

In addition to mismatch repair and other cellular functions, the mismatch repair genes have recently been shown to be repressed in response to environmental stresses, such as hypoxia, benzo[ a ]pyrene, inflammation and even tumor microenvironment [ Mihaylova et al., 2003 ; Bindra and Glazer, 2007 ; Nakamura et al., 2008 ; Edwards et al., 2009 ; Chen et al., 2013 ]. It remains to be seen whether other exogenous stresses can also suppress the expression of MMR genes.

Interstrand cross-link repair (ICL)

Interstrand crosslinks are lesions in which two bases from complementary strands are covalently linked due to damage to the DNA from crosslinking agents such as platinum compounds, nitrogen mustards, MMC, psoralens and alkylating agents [ Clauson et al., 2013 ]. Additional modifications from these crosslinking agents include bases monoadducts, intrastrand crosslinks, and DNA-protein crosslinks. These lesions are recognized and repaired by the Fanconi anemia (FA) proteins. Mutations in the FA genes are the cause of the autosomal recessive FA disorder. FA disorder is a heterogeneous and rare genetic disorder characterized with a high frequency of hematological abnormalities, congenital anomalies and a general predisposition to cancers [ Kee and D’Andrea, 2012 ]. Classically, FA is diagnosed by assessing cellular hypersensitivity—chromosomal breaks and chromosomal radial formations—to DNA ICL agents such as diepoxybutane (DEB) and MMC [ D’Andrea, 2010 ]. In addition, DEB-induced chromosome breakage assay is widely used for the primary diagnosis of FA [ Auerbach, 1993 ].

Interstrand crosslink repair is initiated by chromatin loading of the FA proteins in a cell cycle-dependent manner [ Mi and Kupfer, 2005 ; Kim et al., 2008 ]. The FA family consists of 21 different functional complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V), which are known to suppress ICL sensitivity [ Bluteau et al., 2016 ; Michl et al., 2016 ]. Upon ICL damage, FANCM is recruited to the damaged site along with FAAP24 (Fanconi Anemia associated protein of 24 kDa) and MFH (histone fold protein complex) [ Ciccia et al., 2007 ; Niedernhofer, 2007 ; Yan et al., 2010 ]. Replication fork remodeling stimulated by MFH and FANCM promotes Holliday junction migration and the creation of ssDNA gaps [ Gari et al., 2008a ; Gari et al., 2008b ; Huang et al., 2010 ]. RPA bound ssDNA signals ATR activation [ Zou and Elledge, 2003 ; Ben-Yehoyada et al., 2009 ]. ATR phosphorylates downstream target CHK1, which in turn phosphorylates FANCE, FANCD2, FANCI and MRN [ Andreassen et al., 2004 ; Smogorzewska et al., 2007 ; Wang et al., 2007a ; Cui et al., 2009 ; Duquette et al., 2012 ]. In a yet unknown way, other FA core complex components (FANCA/B/C/E/F/G/L/T) assemble at the damaged site and activate the phosphorylated FANCI–FANCD2 heterodimer through FANCL-mediated monoubiquitination [ Smogorzewska et al., 2007 ]. This activation of FANCI-D2 marks as the major activation switch for the FA pathway [ Wang, 2008 ; Tomida et al., 2013 ]. Subsequently, excision of the DNA strand (5′ and 3′) of the lesion is coordinated by structure specific endonucleases—XPF-ERCC1, MUS8-EME1, SLX4-SLX1, FAN1, SNM1A/SNM1B—in an as-yet unclear fashion [ Clauson et al., 2013 ]. Next, depending upon the proliferation state of the cells, ICL repair bifurcates into either of the two pathways below.

In replicating cells, the presence of ICL stalls the ongoing replication on the leading strand, as well as on the 5′ end of the lagging strand at some distance from the lesion [ Raschle et al., 2008 ; Knipscheer et al., 2009 ]. Next, XPF-ERCC1 and SNM1A induce incisions on either side of the lesion that unhook the ICL from the lagging strand, thereby producing a gap [ Wang et al., 2011 ]. The leading strand with the ICL becomes the template for new DNA synthesis—by TLS polymerases POL ι, POL κ, POL ν and REV1—that proceeds up to the lesion, bypasses it, and extends beyond the lesion until it reaches the first downstream Okazaki fragment [ Minko et al., 2008 ; Raschle et al., 2008 ; Yamanaka et al., 2010 ; Ho et al., 2011 ; Klug et al., 2012 ]. After this step, the 3′ overhang of the leftover lagging strand invades the newly synthesized strand in a RAD51-dependent manner in a tightly coordinated manner [ Long et al., 2011 ]. Interestingly, resolution of this HR intermediate depends on the FANCD2-FANCI complex. NER pathway eventually removes the ICL hook that was still hanging on to the leading strand.

In non-replicating cells, ICL repair of psoralen, MMC, cisplatin, and alkyl ICLs depend on NER and TLS polymerases such as REV1 and POL ζ [ Clauson et al., 2013 ]. Helix-distorting lesions are recognized by both the GG-NER and the TC-NER pathways to initiate repair, although some lesions such as cisplatin may escape recognition [ Enoiu et al., 2012 ]. After lesion recognition, the components of the NER pathway are known to cut only the 5′ side of the lesion, with further incisions possibly aided by the MutSβ complex create a ssDNA-gap [ Bessho et al., 1997 ; Mu et al., 2000 ; Smeaton et al., 2008 ; Zhao et al., 2009 ]. Next, the error-prone TLS polymerase synthesize across the gap and finally a second round of NER removes the ICL hook on the other strand [ Clauson et al., 2013 ].

Recent studies provide a striking evidence of crosstalk between the FA and other repair pathways. For example, the FA pathway suppresses non-homologous end joining (NHEJ) by interacting with CtIP, and recruiting the NHEJ-inhibiting molecules—PARP1 and RAD18 to the DNA [ Saberi et al., 2007 ; Ceccaldi et al., 2016a ]. Similarly, inhibition of NHEJ components alleviates the sensitivity of FA deficient cells to crosslinking agents, while the same FA deficient cells show enrichment of 53BP1, RIF1 and RAP80 components at damaged chromatin [ Adamo et al., 2010 ; Pace et al., 2010 ; Ceccaldi et al., 2016b ; Renaud et al., 2016 ]. A second intriguing example of the FA pathway’s crosstalk is its undefined role in promoting alternate end joining events, as seen in patients with FANCA mutations who lack immunoglobulin class switch recombination. In addition, loss of FANCD2 confers a synthetic lethal phenotype in POL θ null mice [ Nguyen et al., 2014 ; Ceccaldi et al., 2015 ; Howard et al., 2015 ]. Finally, the FA pathway has now been implicated in trinucleotide repeat instability [ Chatterjee N., 2016 ].

Translesion Synthesis (TLS)

Translesion synthesis is carried out by highly conserved TLS polymerases. TLS polymerases are specialized DNA polymerases that can replicate opposite and past aberrant DNA lesions in a relatively lower fidelity manner than replicative DNA polymerases [ Sale, 2013 ]. If incorrect nucleotides were incorporated by TLS polymerases, they would become mutations in the next round of replication, which propel tumorigenesis and disease, but can also contribute to the overall fitness and evolution of organisms. A total of eleven TLS polymerases are known (REV1, POL η, POL ι, POL κ, POL ζ, POL μ, POL λ, POL β, POL ν, POL θ), which are distributed in four families (Y, B, X and A) and PrimPol ( Table 1 ). Although all TLS polymerases are less accurate than replicative polymerases, certain TLS polymerases are able to copy relatively accurately over certain cognate lesions. For example, cyclobutane thymine-thymine CPDs are cognate lesions for POL η ( Table 1 ). The frequency of DNA synthesis errors during translesion synthesis depends on several factors, such as whether the lesion is a cognate for the particular TLS DNA polymerase, the biochemical characteristics of the particular TLS polymerase and the DNA sequence context [ Pages and Fuchs, 2002 ; McCulloch et al., 2004 ; Waters and Walker, 2006 ]. XPV patients, who exhibit a photosensitive phenotype with a high incidence of skin cancer, highlight the physiological significance of certain TLS DNA polymerases bypassing particular lesions. These patients lack the POL η enzyme and are highly susceptible to UV radiation because alternate TLS polymerases (POL ι and POL κ) instead bypass the UV-induced cyclobutane dimers (CPD) in an error-prone fashion [ Yamada et al., 2000 ; Sweasy et al., 2006 ; Wang et al., 2007b ; Ziv et al., 2009 ].

The TLS polymerases’ fascinating ability to help cells tolerate DNA damage arises from their structural and biochemical features [ Rothwell and Waksman, 2005 ; Pavlov et al., 2006 ; Waters and Walker, 2006 ]. Unique functional attributes of TLS polymerases that distinguishes them from the classical replicative polymerases, stems from their discrete physical features. Notable features include the very limited sequence homology to replicative DNA polymerases, the absence of a 3′-5′ exonuclease domain to proofread incoming nucleotides, and their smaller thumb and finger domains, which make fewer contacts with the DNA than those found in replicative DNA polymerases [ Rothwell and Waksman, 2005 ; Waters and Walker, 2006 ; Sale, 2013 ]. These structural differences orient the thumb, fingers, palm, and little finger catalytic domains into a relatively larger open active site, while being aided by other physical features such as the polymerase-associated domain (PAD), wrist, and N-clasp region found in Y Family DNA polymerases that facilitate additional DNA binding. Together, these structural features provide the TLS polymerases with a unique architecture that enable them to bypass DNA damage or fill ssDNA gaps [ Trincao et al., 2001 ; Ling et al., 2003 ; Lone et al., 2007 ; Jansen et al., 2009a ; Jansen et al., 2009b ].

Two models have been proposed to explain the DNA lesion bypass process via translesion synthesis. In the polymerase switch model, TLS polymerases come together sequentially in a two-step process to replicate pass the DNA lesion at a stalled replication fork. First, an ‘inserter’ TLS enzyme, usually a POL η, POL ι, or POL κ, and less often REV1 or POL ζ, incorporates a nucleotide opposite the DNA lesion [ Korzhnev and Hadden, 2016 ]. In the second step, an extender TLS enzyme, a role usually fulfilled by POL ζ exclusively but in some cases by POL κ, replaces the inserter polymerase and extends the primer-template termini [ Washington et al., 2002 ; Yuji Masuda, 2016 ]. This two-step model is proposed to direct both the error-free and error-prone translesion DNA synthesis across the damage [ Shachar et al., 2009 ]. The central molecule that orchestrates both the insertion and extension step is REV1, and by way of its unique scaffolding function facilitates an assemblage of the TLS polymerases by binding to an RIR-containing polymerase—POL η, POL ι, or POL κ—via one interface, and also to POL ζ 4 (REV3-REV7-POLD2-POLD3), via a second interface, a central step in this model’s execution [ Wojtaszek et al., 2012a ; Wojtaszek et al., 2012b ]. Moreover, POLD3, which is part of the POL ζ 4 complex, interacts with REV1 via its RIR, thereby assisting the switch from RIR directed insertion to POL ζ 4 -mediated extension during damage bypass [ Pustovalova et al., 2016 ].

In the gap-filling model, single strand gaps left behind by replicative polymerases during replication or via an incomplete DNA repair process, such as during immunoglobulin gene hypermutation, are the targets of TLS synthesis [ Sale et al., 2009 ]. Usually, these type of TLS events are expected to fall outside of the S phase, but based on the type of DNA lesion, a cell-cycle independence is sometimes conferred [ Quinet et al., 2016 ]. Using a gapped plasmid assay, it has been shown that TLS is as high or higher in G2 compared to S phase in human cells, with slightly higher amounts of POL η in G2 compared to S phase of the cell cycle [ Diamant et al., 2012 ]. An exact order of events for a gap-TLS is still unknown, with only a few isolated studies implying the role of TLS polymerases in gap filling. For example, REV1 is very important in mouse cells for synthesis across post-replicative gaps where REV1 gets recruited to the gaps by the 5′-end, unlike the gap-filling step of NER, where POL κ is the polymerase of choice [ Ogi and Lehmann, 2006 ; de Groote et al., 2011 ; Sale, 2013 ]. Likewise, REV3 engages in TLS across gaps opposite 6-4 photoproducts [ Quinet et al., 2016 ], all suggestive of a role of TLS at replicating across ssDNA gaps.

In addition to their traditional DNA damage bypass functions, TLS polymerases are now known to play a role in other cellular pathways. For instance, as previously discussed, TLS polymerases are required for ICL repair and can also play role in the BER and NER pathways to synthesize new DNA after the excision step. Exogenous stressors—for example UV-C, MNNG, and BPDE—regulate the transcriptional expression of POL η, POL ι, POL κ and POL ζ [ Zhu et al., 2003 ; Yu et al., 2004 ; Liu and Chen, 2006 ; Zhu et al., 2010 ; Zhu et al., 2012 ]. Likewise, an HSP90 inhibitor reduces expression of REV1 and POL η in human cells, indicating an evolutionary regulation of these polymerases [ Sekimoto et al., 2010 ; Pozo et al., 2011 ]. Interestingly, the TLS polymerases, REV1 and REV3, were also implicated in the development of chemoresistance in human cells and mice models, opening the possibility for a whole new class of promising chemotherapeutic drugs [ Doles et al., 2010 ; Xie et al., 2010 ; Xu et al., 2013 ].

Repair of DNA breaks

Single stranded break repair (ssbr).

Single strand breaks (SSBs) are often generated from oxidative damage to the DNA, from abasic sites, or from erroneous activity of the DNA topoisomerase 1 (TOP1) enzyme [ Wang, 2002 ; Hegde et al., 2008 ]. Unresolved SSBs often collapse DNA replication, stall ongoing transcription, and effect PARP1 activation, which releases cellular NAD + , ATP and apoptosis inducing factor (AIF) in cells [ Zhou and Doetsch, 1993 ; Heeres and Hergenrother, 2007 ] At least two human genetic disorders, spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-oculomotor apraxia 1 (AOA1), are associated with an abortive SSBR. These patients often manifest genetic instability and high incidence of cancers [ El-Khamisy et al., 2005 ; Reynolds et al., 2009 ]. SSBR is predicted to occur through three different pathways depending on the source of SSB.

In the long patch SSBR pathway, SSBs are transiently detected by PARP1, which undergoes a rapid cycle of poly(ADP) ribosylation and dissociates to detect the next SSB [ D’Amours et al., 1999 ; Davidovic et al., 2001 ]. After this, the ends undergo end processing by the apurinic-apyrimidic endonuclease 1 APE1, PNKP (polynuceotide kinase 3′-phosphate) and aprataxin (APTX) [ McKinnon and Caldecott, 2007 ]. Next, FEN1 removes the damaged 5′ termini aided by PARP1 and PCNA, leaving behind a ssDNA gap, which is filled by POL β, in combination with POL δ/ε. The final step of ligation is carried out by the LIG1, which is dependent on the presence of PCNA and XRCC1 [ Lan et al., 2004 ; Mortusewicz et al., 2006 ; McKinnon and Caldecott, 2007 ]. In the short patch SSBR pathway, SSBs generated during the BER are recognized by APE1 followed by a similar end-processing pathway as the long patch repair. The gap-filling step, however, is only carried out by POL β enzyme, followed by LIG3-catalyzed ligation [ McKinnon and Caldecott, 2007 ]. Finally, the TOP1-SSB pathway is a variant of the PARP1-dependent long patch repair in which the end-processing is carried out by the TDP1 (tyrosyl-DNA phosphodiesterase 1) enzyme that removes the TOP1 from the 3′-end [ Caldecott, 2008 ].

Double strand break repair (DSBR)

Highly toxic DSBs are induced by various chemical and physical DNA damaging agents [ Pfeiffer et al., 2000 ]. Unresolved DSBs are implicated in various human disorders and cancers [ Jackson and Bartek, 2009 ]. We will briefly discuss the two major pathways—homologous recombination (HR) and non-homologous end joining (NHEJ)—that organisms have evolved to resolve the DSBs. Chromatin modification is the first event that registers the presence of a DSB and triggers a cascade of events including ATM activation, targeted phosphorylation of H2AX, chromatin PARylation, MDC1 recruitment and finally recruitment of 53BP1 and BRCA1 [ Rogakou et al., 1998 ; Rothkamm et al., 2003 ; Gottschalk et al., 2009 ; Chou et al., 2010 ; Lukas et al., 2011 ; Price and D’Andrea, 2013 ; Liu et al., 2014 ]. Interestingly, both 53BP1 and BRCA1 exhibit an antagonistic influence on each other and 53BP1 depletion rescues embryonic lethality of BRCA1 null mice [ Xie et al., 2007 ; Cao et al., 2009 ; Bunting et al., 2010 ].

In the NHEJ pathway of DSBR, 53BP1 plays an important regulatory role by recruiting the NHEJ components to the break site, activating checkpoint signaling and facilitating synapsis of the two ends [ Panier and Boulton, 2014 ]. The Ku (Ku70 and Ku80) heterodimer is the first to recognize and bind the DSBs within seconds to prevent end resection and serves as a scaffold to recruit other NHEJ components [ Pang et al., 1997 ; Mari et al., 2006 ; Soutoglou et al., 2007 ; Mimitou and Symington, 2010 ]. Other recruited components include DNA-PKcs, XRCC4, LIG4 and XLF (XRCC4-like factor), APLF (Aprataxin-and-PNK-like factor) [and also TdT (terminal deoxynucleotidyl transferase) in lymphocytes] [ Gottlieb and Jackson, 1993 ; Nick McElhinny et al., 2000 ; Costantini et al., 2007 ; Yano et al., 2008 ; Grundy et al., 2013 ]. Recent studies indicate that the order of recruitment of these components may depend on the complexity of DNA damage; for instance, DNA-PKcs recruitment depends on the nature of the break [ Mari et al., 2006 ; Yano and Chen, 2008 ]. However, once DNA-PKcs gets recruited, it is activated in a DNA dependent manner; it pushes Ku inwardly on the DNA and then phosphorylates other nearby components, including autoautophosphorylating itself [ Gottlieb and Jackson, 1993 ; Yoo and Dynan, 1999 ; Weterings and Chen, 2008 ]. At the same time, XRCC4 is believed to help stabilize the NHEJ complex by tethering the ends and acting as an additional scaffold with Ku to recruit other components [ Malivert et al., 2010 ; Hammel et al., 2011 ; Andres et al., 2012 ]. Once the ends are bridged and stabilized, Artemis, PNKP, APLF, WRN, Aprataxin and Ku initiate DNA end processing, which involves removing groups that are blocking the ends and resecting the resultant naked strands [ Ma et al., 2002 ; Bernstein et al., 2005 ; Ahel et al., 2006 ; Perry et al., 2006 ; Roberts et al., 2010 ; Li et al., 2011 ]. The gaps left behind after resection are filled by family X polymerases in a template-dependent (POL μ) or template-independent (POL λ) manner [ Ramadan et al., 2004 ; Roberts et al., 2010 ]. LIG4 joins the ends and completes the NHEJ process [ Grawunder et al., 1997 ].

The HR pathway consist of a set of related sub-pathways that utilize DNA strand invasion and template-directed DNA repair synthesis to effect a high-fidelity repair [ Li and Heyer, 2008 ]. In addition to the traditional DSBR-induced HR pathway, synthesis-dependent strand annealing (SDSA) and break-induced repair (BIR) are two other variations following the HR premise [ Li and Heyer, 2008 ]. Here, we will very briefly summarize the HR pathway of DSBR.

The MRN (MRE11-RAD50-NBS1) complex initiates HR at a DSB, where it recognizes and binds the DSB and then recruits ATM and TIP60 to the DNA [ Sun et al., 2005 ; Stracker and Petrini, 2011 ]. Activated ATM (from TIP60) phosphorylates H2AX, which then serves as an anchor for MDC1 [ Bhatti et al., 2011 ]. Next, MDC1 is phosphorylated by ATM, and the phosphorylated MDC1 functions as a scaffold to bring in the ubiquitin E3 ligases RNF8 and RNF168 [ Altmeyer and Lukas, 2013b ]. Both of these E3 ligases ubiquitinate H2AX, which then serves as a docking site for 53BP1 and BRCA1. In the S/G2 phase where HR is predominant, BRCA1 (recruited by ubiquitinated chromatin) successfully counteracts 53BP1 and initiates ubiquitination of the downstream component, CtIP [ Yu et al., 2006 ; Chapman et al., 2012 ]. At this time, the other HR components, RPA, and RAD51 proteins make their way on to the DNA.

The next step of end resection involves a 5′-to-3′ nucleolytic degradation to generate 3′ overhangs, committing cells to the HR pathway. Initial resection occurs by the endonuclease activity of MRN, with the help of CtIP, followed by long-range resection by EXO1 or BLM together with DNA2 [ Chen et al., 2008 ; Nimonkar et al., 2011 ]. Next, RPA coats the 3′ overhang, which is then displaced by RAD51, generating a nucleoprotein filament. BRCA2 and PALB2 aid in the formation of the nucleoprotein filament formation that invades a nearby duplex DNA forming a D-loop [ Zhang et al., 2009 ; Holloman, 2011 ]. Several other proteins function together at this step. For the strand to invade the template DNA, RAD54 and RAD54B remove RAD51 and allow the 3′-OH group to prime synthesis by Polymerases δ, κ and ν [ Mazin et al., 2010 ; Sebesta et al., 2013 ]. If the new DNA synthesis stops after a limited distance, as is the case in SDSA, the RTEL1 enzyme dissolves the D-loop [ Barber et al., 2008 ]. Otherwise, the Holliday junction is collectively processed by the BLM-TOPOIII-RMI1-RMI2 complex, GEN1 endonuclease, the MUS81-EME1 complex and the SLX1-SLX4 complex [ Chang et al., 2008 ; Ciccia et al., 2008 ; Xu et al., 2008 ; Fekairi et al., 2009 ; Rass et al., 2010 ].

DNA damage and telomeres

Telomeres are well-conserved nucleoprotein structures found at the end of linear chromosomes that help differentiate normal chromosomal ends from DSBs [ Longhese, 2008 ; Shammas, 2011 ]. Telomeric DNA consists of tandem repetitive DNA (TTAGGG in humans), where the G-rich strand (also called the G-tail), bound by sheltrin protein POT1 (protection of telomeres 1), extends beyond the complementary C-rich strand and invades into the double-stranded telomeric DNA. The t-loop thus generated complexes with other sheltrin proteins such as TRF1 (telomeric-repeat binding factor 1), TRF2, TIN2 (TRF-interacting protein 2), the transcriptional repressor/activator protein RAP1, and the TPP1 (POT1- and TIN2- organizing protein), which together prevent the chromosomal ends from being recognized as DNA damage [ Takai et al., 2003 ; d’Adda di Fagagna et al., 2004 ; Liu et al., 2004 ; de Lange, 2005 ]. In addition, telomeric DNA is replicated and maintained by a specialized ribonucleoprotein complex called telomerase [composed of a telomere RNA component (TERC) and a telomere reverse transcriptase (TERT)], which is the only positive regulator of telomere length [ Bachand et al., 2001 ; Blasco, 2003 ]. A decline in telomerase activity contributes to telomere attrition, which is associated with aging, cancer and several inherited bone marrow failure (IBMF) disorders [ Chang and Harley, 1995 ; Shay et al., 2001 ; Alter et al., 2015 ].

Deprotected telomeres elicit a DNA damage response, recruiting DSBR components that attempt to repair the exposed ends, causing deleterious nucleolytic degradation, recombination, and chromosomal fusions [ Longhese, 2008 ]. For example, short telomeres often assemble DDR factors such as 53BP1, ATM, γH2AX, and MRE11 as foci, called Telomere Dysfunction-Induced Foci (TIF), which are highly prone to NHEJ-mediated end-to-end fusion [ Takai et al., 2003 ; Hewitt et al., 2012 ; Marcand, 2014 ]. Surprisingly, telomere maintenance requires the presence of some of the same components of DSBR/NHEJ components—for example, Ku and the MRN complex—complicating our understanding of the exact mechanism of telomere stability [ Maser and DePinho, 2004 ; Marcand, 2014 ]. Establishing the dynamics of this telomere biology is an active area of research.

Recently, several environmental toxins have been implicated in telomere shortening. For example, tobacco smoke causes telomere shortening via oxidative stress [ Valdes et al., 2005 ; McGrath et al., 2007 ; Song et al., 2010 ; Babizhayev and Yegorov, 2011 ]. Obesity has also been associated with accelerated shortening of telomeres in adipose tissue of mice, where levels of ROS were high [ Song et al., 2010 ]. Likewise, white blood cells of obese women harbor shorter telomeres than lean women [ Valdes et al., 2005 ]. Genotoxic stressors such as certain pollutants (e.g. toluene and benzene, and PAHs) are also associated with telomere shortening [ Hoxha et al., 2009 ; Pavanello et al., 2010 ; Trusina, 2014 ]. Finally, everyday stresses, including psychological stress, is known to shorten telomeres, whereas meditation and mindfulness may bring about an opposite effect [ Epel et al., 2004 ; Cherkas et al., 2006 ; Simon et al., 2006 ; Epel et al., 2009 ; Mathur et al., 2016 ]. Critically shortened telomeres are associated with aging and cancer [ Shammas, 2011 ].

In conclusion, DNA is continually being exposed to both endogenous and exogenous DNA damaging agents that chemically modify the DNA constituents. Unresolved DNA damages are implicated in human diseases and cancers. However, robust DNA repair and damage tolerance pathways help remove or tolerate the lesions to allow survival ( Figure 4 ). An understanding of these pathways helps evaluate possible toxic exposures and design strategies to control deleterious consequences on human health.

Acknowledgments

The writing of this review was supported by National Institute of Environmental Health Sciences grants ES-015818 to G.C.W. and P30 ES-002109 to the MIT Center for Environmental Health Sciences. G.C.W. is an American Cancer Society Professor. Nimrat Chatterjee and Graham Walker wrote the manuscript.

There are no conflicts of interests.

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Genetics is the branch of science concerned with genes, heredity, and variation in living organisms. It seeks to understand the process of trait inheritance from parents to offspring, including the molecular structure and function of genes, gene behaviour in the context of a cell or organism (e.g. dominance and epigenetics), gene distribution, and variation and change in populations.

Menopause age shaped by genes that influence mutation risk

By mining large-population genetic data sets, researchers identify the key factors controlling menopause timing, and reveal a close connection between reproductive longevity, cancer risk and new mutations in children.

• Anne Goriely

Rapa Nui’s population history rewritten using ancient DNA

By analysing the ancient genomes of individuals from Rapa Nui, researchers have overturned a contentious theory that the remote Pacific island experienced a self-inflicted population collapse before European colonization.

• Stephan Schiffels
• Kathrin Nägele

Humans have evolved to digest starch more easily since the advent of farming

The region of the human genome that harbours genes encoding amylase enzymes, which are crucial for starch digestion, shows extensive structural diversity. Amylase genes have been duplicated and deleted several times in human history, and structures that contain duplicated versions of the genes were favoured by natural selection after the advent of agriculture.

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Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy

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Sequence variants influencing the regulation of serum IgG subclass levels

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Sexually dimorphic renal expression of mouse Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b

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Dna gone viral, science | brain cell mutations from mitochondria may shorten life.

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Mitochondria, the tiny powerhouses that energize human cells and have their own unique DNA, can also be troublemakers. In brain cells, mitochondria can transfer snippets of their DNA into the cells’ nuclei, where they may enter the genome and cause mutations. In a new study published Aug. 22 in PLOS Biology , researchers at Columbia University and the University of Michigan found that these mitochondria DNA transfers, previously thought to be extremely rare, are relatively frequent. They also appear to be more common in people who die younger. The scientists collected blood and brain tissue samples from nearly 1,200 deceased people. They found that the majority of mitochondrial DNA insertions in brain tissue were located in the prefrontal cortex, the part of the brain responsible for cognitive ability. Analysis revealed that individuals with a higher number of these insertions in the prefrontal cortex died earlier than did those with fewer insertions. For individuals with no cognitive impairment, every two additional insertions correlated with dying a decade earlier. Among people who had dementia, though, the researchers found no such link between mutations and age at death. They noted that while the results suggest these brain mutations are harmful, they do not cause Alzheimer’s.

Fast physiology

Intermittent fasting provides health benefits like lowered blood pressure, but what happens when chomping down resumes? New evidence suggests breaking fast could be a double-edged sword: It promotes both cell regeneration and tumor formation. An MIT-led team of researchers evaluated intestinal stem cell proliferation in mice during a 24-hour fast and a subsequent refeeding. They found that stem cell regeneration peaked at the end of the 24-hour refeeding period. The team also discovered the stem cells activate a cellular signaling pathway that bolsters their growth, producing proteins and poly­amines needed for cells to grow and multiply. But the peaked cell regeneration came with baggage—the growth of precancerous cells. Turning on a cancer-causing gene during the refeeding period resulted in far greater precancerous growths than when the gene was turned on during the fasting period. More studies are needed to see if the findings, published Aug. 21 in Nature , are applicable to humans. —H.F.

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Tablets and tempers

Screen time can temporarily right a toddler’s bad mood, but the long-term effects might not be worth it. A study published Aug. 12 in JAMA Pediatrics noted a link between early childhood tablet use and outbursts of anger. Greater tablet use at 3½ years old was associated with significantly increased fits of anger and frustration at 4½, which in turn was linked to increased tablet use at 5½ years old. Lead author Caroline Fitzpatrick said parents should swap the digital pacifier for physical activities and other forms of play that encourage self-regulation. —H.F.

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Heather is a science correspondent for WORLD. She is a graduate of World Journalism Institute, the University of Maryland, and Carnegie Mellon University. She has worked in both food and chemical product development, and currently works as a research chemist. Heather resides with her family in Pittsburgh, Pa.

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