DNA repair: Difference between revisions

{{shortShort description|Cellular mechanism}}

{{forFor|the journal|DNA Repair (journal)}}

'''DNA repair''' is a collection of processes by which a [[cell (biology)|cell]] identifies and corrects damage to the [[DNA]] molecules that encodesencode its [[genome]].<ref name="Jackson-Bartek-2009">{{cite journal|title=Nature Reviews Series: DNA damage|journal=[[Nature Reviews Molecular Cell Biology]]|date=5 Jul 2017|url=https://www.nature.com/collections/hwnqqcstyj|access-date=7 Nov 2018}}</ref> In human cells, both normal [[metabolism|metabolic]] activities and environmental factors such as [[radiation]] can cause DNA damage, resulting in tens of thousands of individual [[molecular lesion]]s per cell per day.<ref name="lodish">{{cite book |vauthors=Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J |year=2004 |title=Molecular Cell Biology of the Cell |page=963 |publisher=WH Freeman |locationedition=New York5th |editionisbn=5th978-0-7167-4366-8 |oclc=53798180}}</ref> Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to [[Transcription (biology)|transcribe]] the [[gene]] that the affected DNA encodes. Other lesions induce potentially harmful [[mutation]]s in the cell's genome, which affect the survival of its daughter cells after it undergoes [[mitosis]]. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular [[apoptosis]] does not occur, irreparable DNA damage may occur, including double-strand breaks and [[Crosslinking of DNA|DNA crosslinkages]] (interstrand crosslinks or ICLs).<ref name="acharya">{{cite journal | vauthors = Acharya PV | title = The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides | journal = Johns Hopkins Medical Journal. Supplement | issue = 1 | pages = 254–60 | year = 1971 | pmid = 5055816 }}</ref><ref name="Bjorksten">{{cite journal | vauthors = Bjorksten J, Acharya PV, Ashman S, Wetlaufer DB | title = Gerogenic fractions in the tritiated rat | journal = Journal of the American Geriatrics Society | volume = 19 | issue = 7 | pages = 561–74 | date = July 1971 | pmid = 5106728 | doi = 10.1111/j.1532-5415.1971.tb02577.x | s2cid = 33154242 }}</ref> This can eventually lead to malignant tumors, or [[cancer]] as per the [[Knudson hypothesis|two -hit hypothesis]].

The rate of DNA repair is dependentdepends on manyvarious factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one thatcan no longer effectively repairs damage incurred torepair its DNA, canmay enter one of three possible states:

# an irreversible state of dormancy, known as [[Cellularcellular senescence|senescence]]

The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence [[life expectancy|life span]] have turned out to be involved in DNA damage repair and protection.<ref name="browner">{{cite journal | vauthors = Browner WS, Kahn AJ, Ziv E, Reiner AP, Oshima J, Cawthon RM, Hsueh WC, Cummings SR | display-authors = 6 | title = The genetics of human longevity | journal = The American Journal of Medicine | volume = 117 | issue = 11 | pages = 851–60 | date = December 2004 | pmid = 15589490 | doi = 10.1016/j.amjmed.2004.06.033 | citeseerx = 10.1.1.556.6874 }}</ref>

The 2015 [[Nobel Prize in Chemistry]] was awarded to [[Tomas Lindahl]], [[Paul Modrich]], and [[Aziz Sancar]] for their work on the molecular mechanisms of DNA repair processes.<ref name="NYT-20151007-wjb">{{cite news |last=Broad |first=William J. | name-list-style = vanc |title=Nobel Prize in Chemistry Awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for DNA Studies |url=https://www.nytimes.com/2015/10/08/science/tomas-lindahl-paul-modrich-aziz-sancarn-nobel-chemistry.html |date=7 October 2015 |work=[[The New York Times]] |access-date=7 October 2015 }}</ref><ref name="NP-20151007">{{cite news |author=Staff |title=The Nobel Prize in Chemistry 2015 – DNA repair – providing chemical stability for life |url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2015/popular-chemistryprize2015.pdf |date=7 October 2015 |work=[[Nobel Prize]] |access-date=7 October 2015 }}</ref>

{{furtherFurther|DNA damage (naturally occurring)|Free radical damage to DNA}}

# ''Thermal disruption'' at elevated temperature increases the rate of [[depurination]] (loss of [[purine]] bases from the DNA backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the [[thermophilic bacteria]], which grow in [[hot springs]] at 40–80&nbsp;°C.<ref>{{cite book |title=Brock Biology of Microorganisms | year=2006|vauthors=Madigan MT, Martino JM | edition=11th |page=136 |publisher=Pearson |isbn=978-0-13-196893-6}}</ref><ref name="Toshihiro">{{cite journal | vauthors = Ohta T, Tokishita SI, Mochizuki K, Kawase J, Sakahira M, Yamagata H |doi=10.3123/jemsge.28.56 |year=2006 |title=UV Sensitivity and Mutagenesis of the Extremely Thermophilic Eubacterium Thermus thermophilus HB27 |journal=Genes and Environment |volume=28 |issue=2 |pages=56–61|doi-access=free |bibcode=2006GeneE..28...56O }}</ref> The rate of depurination (300 [[purine]] residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an [[adaptive response]] cannot be ruled out.

Senescence, an irreversible process in which the cell no longer [[mitosis|divides]], is a protective response to the shortening of the chromosome ends, called [[telomeres]]. The telomeres are long regions of repetitive [[noncoding DNA]] that cap chromosomes and undergo partial degradation each time a cell undergoes division (see [[Hayflick limit]]).<ref name="braig">{{cite journal | vauthors = Braig M, Schmitt CA | title = Oncogene-induced senescence: putting the brakes on tumor development | journal = Cancer Research | volume = 66 | issue = 6 | pages = 2881–842881–4 | date = March 2006 | pmid = 16540631 | doi = 10.1158/0008-5472.CAN-05-4006 | doi-access = free }}</ref> In contrast, [[G0 phase|quiescence]] is a reversible state of cellular dormancy that is unrelated to genome damage (see [[cell cycle]]). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,<ref name="Lynch">{{cite journal | vauthors = Lynch MD | title = How does cellular senescence prevent cancer? | journal = DNA and Cell Biology | volume = 25 | issue = 2 | pages = 69–78 | date = February 2006 | pmid = 16460230 | doi = 10.1089/dna.2006.25.69 }}</ref> which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth [[cellular signaling]]. Unregulated cell division can lead to the formation of a tumor (see [[cancer]]), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.<ref name="pmid17667954">{{cite journal | vauthors = Campisi J, d'Adda di Fagagna F | s2cid = 15664931 | title = Cellular senescence: when bad things happen to good cells | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 9 | pages = 729–40 | date = September 2007 | pmid = 17667954 | doi = 10.1038/nrm2233 }}</ref>

{{mainMain|DNA damage (naturally occurring)#Repair of damaged DNA}}

Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of [[pyrimidine dimer]]s upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The [[photoreactivation]] process directly reverses this damage by the action of the enzyme [[photolyase]], whose activation is obligately dependent on energy absorbed from [[electromagnetic spectrum|blue/UV light]] (300–500&nbsp;nm [[wavelength]]) to promote catalysis.<ref name="Sancar">{{cite journal | vauthors = Sancar A | title = Structure and function of DNA photolyase and cryptochrome blue-light photoreceptors | journal = Chemical Reviews | volume = 103 | issue = 6 | pages = 2203–37 | date = June 2003 | pmid = 12797829 | doi = 10.1021/cr0204348 }}</ref> Photolyase, an old enzyme present in [[bacteria]], [[fungi]], and most [[animals]] no longer functions in humans,<ref>{{cite journal | vauthors = Lucas-Lledó JI, Lynch M | title = Evolution of mutation rates: phylogenomic analysis of the photolyase/cryptochrome family | journal = Molecular Biology and Evolution | volume = 26 | issue = 5 | pages = 1143–53 | date = May 2009 | pmid = 19228922 | pmc = 2668831 | doi = 10.1093/molbev/msp029 }}</ref> who instead use [[nucleotide excision repair]] to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the enzyme methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called [[AGT II|ogt]]. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is [[stoichiometric]] rather than [[catalytic]].<ref name="watson">{{cite book |vauthors=Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R |year=2004 |title=Molecular Biology of the Gene |publisher=Pearson Benjamin Cummings; CSHL Press |edition=5th |at=Ch. 9, 10 |oclc=936762772 }}</ref> A generalized response to methylating agents in bacteria is known as the [[adaptive response]] and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.<ref name="Volkert">{{cite journal | vauthors = Volkert MR | title = Adaptive response of Escherichia coli to alkylation damage | journal = Environmental and Molecular Mutagenesis | volume = 11 | issue = 2 | pages = 241–55 | year = 1988 | pmid = 3278898 | doi = 10.1002/em.2850110210 | bibcode = 1988EnvMM..11..241V | s2cid = 24722637 }}</ref> The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.

# [[Base excision repair]] (BER): damaged single bases or nucleotides are most commonly repaired by removing the base or the nucleotide involved and then inserting the correct base or nucleotide. In base excision repair, a [[DNA glycosylase|glycosylase]]<ref name = "Willey">{{cite book | vauthors = Willey J, Sherwood L, Woolverton C |date= 2014|title= Prescott's Microbiology |location= New York |publisher= McGraw Hill |page= 381 |isbn= 978-0-07-3402-40340240-6}}</ref> enzyme removes the damaged base from the DNA by cleaving the bond between the base and the deoxyribose. These enzymes remove a single base to create an apurinic or apyrimidinic site ([[AP site]]).<ref name = "Willey" /> Enzymes called [[AP endonuclease]]s [[Nick (DNA)|nick]] the damaged DNA backbone at the AP site. DNA polymerase then removes the damaged region using its 5’5' to 3’3' exonuclease activity and correctly synthesizes the new strand using the complementary strand as a template.<ref name = "Willey" /> The gap is then sealed by enzyme DNA ligase.<ref name=":1">{{Cite book|title=i Genetics |last=Russell |first=Peter | name-list-style = vanc |publisher=Pearson|year=2018|isbn=978-93-325-7162-4|location=Chennai|pages=186}}</ref>

# [[Nucleotide excision repair]] (NER): bulky, helix-distorting damage, such as [[pyrimidine dimer]]ization caused by UV light is usually repaired by a three-step process. First the damage is recognized, then 12-24 nucleotide-long strands of DNA are removed both upstream and downstream of the damage site by [[endonuclease]]s, and the removed DNA region is then resynthesized.<ref name = "Reardon">{{cite book | vauthors = Reardon JT, Sancar A | title = DNA Repair, Part A | chapter = Purification and characterization of Escherichia coli and human nucleotide excision repair enzyme systems | series = Methods in Enzymology | volume = 408 | pages = 189–213 | date = 2006 | pmid = 16793370 | doi = 10.1016/S0076-6879(06)08012-8 | isbn = 9780121828134978-0-12-182813-4 }}</ref> NER is a highly evolutionarily conserved repair mechanism and is used in nearly all eukaryotic and prokaryotic cells.<ref name = "Reardon" /> In prokaryotes, NER is mediated by [[UvrABC endonuclease|Uvr proteins]].<ref name = "Reardon"/> In eukaryotes, many more proteins are involved, although the general strategy is the same.<ref name = "Reardon"/>

# [[Mismatch repair]] systems are present in essentially all cells to correct errors that are not corrected by [[Proofreading (biology)|proofreading]]. These systems consist of at least two proteins. One detects the mismatch, and the other recruits an endonuclease that cleaves the newly synthesized DNA strand close to the region of damage. In ''E. coli '', the proteins involved are the Mut class proteins: MutS, MutL, and MutH. In most Eukaryotes, the analog for MutS is MSH and the analog for MutL is MLH. MutH is only present in bacteria. This is followed by removal of damaged region by an exonuclease, resynthesis by DNA polymerase, and nick sealing by DNA ligase.<ref name = "Berg">{{cite book | vauthors = Berg M, Tymoczko J, Stryer L | date = 2012 | title = Biochemistry 7th edition | location = New York | publisher = W.H. Freeman and Company | page = 840 | isbn = 9781429229364978-1-4292-2936-4 }}</ref> {{Clear}}

Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to [[Chromosomal rearrangement|genome rearrangements]]. In fact, when a double-strand break is accompanied by a cross-linkage joining the two strands at the same point, neither strand can be used as a template for the repair mechanisms, so that the cell will not be able to complete mitosis when it next divides, and will either die or, in rare cases, undergo a mutation.<ref name="acharya">{{cite journal | vauthors = Acharya PV | title = The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides | journal = Johns Hopkins Medical Journal. Supplement | issue = 1 | pages = 254–60 | year = 1971 | pmid = 5055816 }}</ref><ref name="Bjorksten">{{cite journal | vauthors = Bjorksten J, Acharya PV, Ashman S, Wetlaufer DB | title = Gerogenic fractions in the tritiated rat | journal = Journal of the American Geriatrics Society | volume = 19 | issue = 7 | pages = 561–74 | date = July 1971 | pmid = 5106728 | doi = 10.1111/j.1532-5415.1971.tb02577.x | s2cid = 33154242 }}</ref> Three mechanisms exist to repair double-strand breaks (DSBs): [[non-homologous end joining]] (NHEJ), [[microhomology-mediated end joining]] (MMEJ), and [[homologous recombination]] (HR):<ref name="watson" /><ref name="pmid16012167">{{cite journal | vauthors = Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA | title = Modulation of DNA end joining by nuclear proteins | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31442–49 | date = September 2005 | pmid = 16012167 | doi = 10.1074/jbc.M503776200 | doi-access = free }}</ref>

# In NHEJ, [[LIG4|DNA Ligase IV]], a specialized [[DNA ligase]] that forms a complex with the cofactor [[XRCC4]], directly joins the two ends.<ref>{{cite journal | vauthors = Wilson TE, Grawunder U, Lieber MR | s2cid = 4422938 | title = Yeast DNA ligase IV mediates non-homologous DNA end joining | journal = Nature | volume = 388 | issue = 6641 | pages = 495–98495–8 | date = July 1997 | pmid = 9242411 | doi = 10.1038/41365 | bibcode = 1997Natur.388..495W | doi-access = free }}</ref> To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.<ref name="Moore and Haber">{{cite journal | vauthors = Moore JK, Haber JE | title = Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae | journal = Molecular and Cellular Biology | volume = 16 | issue = 5 | pages = 2164–73 | date = May 1996 | pmid = 8628283 | pmc = 231204 | doi = 10.1128/mcb.16.5.2164 }}</ref><ref>{{cite journal | vauthors = Boulton SJ, Jackson SP | title = Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways | journal = The EMBO Journal | volume = 15 | issue = 18 | pages = 5093–103 | date = September 1996 | pmid = 8890183 | pmc = 452249 | doi = 10.1002/j.1460-2075.1996.tb00890.x }}</ref><ref name="Wilson and Lieber">{{cite journal | vauthors = Wilson TE, Lieber MR | title = Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase beta (Pol4)-dependent pathway | journal = The Journal of Biological Chemistry | volume = 274 | issue = 33 | pages = 23599–609 | date = August 1999 | pmid = 10438542 | doi = 10.1074/jbc.274.33.23599 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Budman J, Chu G | title = Processing of DNA for nonhomologous end-joining by cell-free extract | journal = The EMBO Journal | volume = 24 | issue = 4 | pages = 849–60 | date = February 2005 | pmid = 15692565 | pmc = 549622 | doi = 10.1038/sj.emboj.7600563 }}</ref> NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher [[eukaryote]]s.<ref name="wang">{{cite journal | vauthors = Wang H, Perrault AR, Takeda Y, Qin W, Wang H, Iliakis G | title = Biochemical evidence for Ku-independent backup pathways of NHEJ | journal = Nucleic Acids Research | volume = 31 | issue = 18 | pages = 5377–88 | date = September 2003 | pmid = 12954774 | pmc = 203313 | doi = 10.1093/nar/gkg728 }}{{Expression of Concern|doi=10.1093/nar/gkaa228|pmid=32239214}}</ref> Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during [[V(D)J recombination]], the process that generates diversity in [[B-cell receptor|B-cell]] and [[T-cell receptor]]s in the [[vertebrate]] [[immune system]].<ref>{{cite journal | vauthors = Jung D, Alt FW | s2cid = 16890458 | title = Unraveling V(D)J recombination; insights into gene regulation | journal = Cell | volume = 116 | issue = 2 | pages = 299–311 | date = January 2004 | pmid = 14744439 | doi = 10.1016/S0092-8674(04)00039-X | doi-access = free }}</ref>

# MMEJ starts with short-range [[DNA end resection|end resection]] by [[MRE11]] nuclease on either side of a double-strand break to reveal microhomology regions.<ref name=Truong>{{cite journal | vauthors = Truong LN, Li Y, Shi LZ, Hwang PY, He J, Wang H, Razavian N, Berns MW, Wu X | display-authors = 6 | title = Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 19 | pages = 7720–257720–5 | date = May 2013 | pmid = 23610439 | pmc = 3651503 | doi = 10.1073/pnas.1213431110 | bibcode = 2013PNAS..110.7720T | doi-access = free }}</ref> In further steps,<ref name="pmid25789972">{{cite journal | vauthors = Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC | title = Homology and enzymatic requirements of microhomology-dependent alternative end joining | journal = Cell Death & Disease | volume = 6 | issue = 3 | pages = e1697 | date = March 2015 | pmid = 25789972 | pmc = 4385936 | doi = 10.1038/cddis.2015.58 }}</ref> [[PARP1|Poly (ADP-ribose) polymerase 1]] (PARP1) is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of [[flap structure-specific endonuclease 1]] (FEN1) to remove overhanging flaps. This is followed by recruitment of [[XRCC1]]–[[LIG3]] to the site for ligating the DNA ends, leading to an intact DNA. MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.<ref name="pmid23565119">{{cite journal | vauthors = Decottignies A | title = Alternative end-joining mechanisms: a historical perspective | journal = Frontiers in Genetics | volume = 4 | pages = 48 | year = 2013 | pmid = 23565119 | pmc = 3613618 | doi = 10.3389/fgene.2013.00048 | doi-access = free }}</ref>

The [[extremophile]] ''[[Deinococcus radiodurans]]'' has a remarkable ability to survive DNA damage from [[ionizing radiation]] and other sources. At least two copies of the genome, with random DNA breaks, can form DNA fragments through [[Annealing (biology)|annealing]]. Partially overlapping fragments are then used for synthesis of [[Homology (biology)#Homology of sequences in genetics|homologous]] regions through a moving [[D-loop]] that can continue extension until complementary partner strands are found. In the final step, there is [[Chromosomal crossover|crossover]] by means of [[RecA]]-dependent [[Homologous recombination#RecBCD pathway|homologous recombination]].<ref name="MRadman">{{cite journal | vauthors = Zahradka K, Slade D, Bailone A, Sommer S, Averbeck D, Petranovic M, Lindner AB, Radman M | s2cid = 4412830 | display-authors = 6 | title = Reassembly of shattered chromosomes in Deinococcus radiodurans | journal = Nature | volume = 443 | issue = 7111 | pages = 569–73 | date = October 2006 | pmid = 17006450 | doi = 10.1038/nature05160 | bibcode = 2006Natur.443..569Z }}</ref>

Translesion synthesis (TLS) is a DNA damage tolerance process that allows the [[DNA replication]] machinery to replicate past DNA lesions such as [[thymine dimer]]s or [[AP site]]s.<ref name="pmid19258535">{{cite journal | vauthors = Waters LS, Minesinger BK, Wiltrout ME, D'Souza S, Woodruff RV, Walker GC | title = Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance | journal = Microbiology and Molecular Biology Reviews | volume = 73 | issue = 1 | pages = 134–54 | date = March 2009 | pmid = 19258535 | pmc = 2650891 | doi = 10.1128/MMBR.00034-08 }}</ref> It involves switching out regular [[DNA polymerase]]s for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication [[processivity]] factor [[PCNA]]. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, [[DNA polymerase eta|Pol η]] mediates error-free bypass of lesions induced by [[ultraviolet|UV irradiation]], whereas [[POLI|Pol ι]] introduces mutations at these sites. Pol η is known to add the first adenine across the [[Pyrimidine dimers#Mutagenesis|T^T photodimer]] using [[Base pair|Watson-Crick base pairing]] and the second adenine will be added in its syn conformation using [[Hoogsteen base pair]]ing. From a cellular perspective, risking the introduction of [[point mutation]]s during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized [[polymerases]] either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although it can cause targeted and semi-targeted mutations.<ref name="pmid18616294">{{cite journal | vauthors = Colis LC, Raychaudhury P, Basu AK | title = Mutational specificity of gamma-radiation-induced guanine-thymine and thymine-guanine intrastrand cross-links in mammalian cells and translesion synthesis past the guanine-thymine lesion by human DNA polymerase eta | journal = Biochemistry | volume = 47 | issue = 31 | pages = 8070–798070–9 | date = August 2008 | pmid = 18616294 | pmc = 2646719 | doi = 10.1021/bi800529f }}</ref> Paromita Raychaudhury and Ashis Basu<ref name="pmid21302943">{{cite journal | vauthors = Raychaudhury P, Basu AK | title = Genetic requirement for mutagenesis of the G[8,5-Me]T cross-link in Escherichia coli: DNA polymerases IV and V compete for error-prone bypass | journal = Biochemistry | volume = 50 | issue = 12 | pages = 2330–382330–8 | date = March 2011 | pmid = 21302943 | pmc = 3062377 | doi = 10.1021/bi102064z }}</ref> studied the toxicity and mutagenesis of the same lesion in ''Escherichia coli'' by replicating a G[8,5-Me]T-modified plasmid in ''E. coli'' with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases.

After DNA damage, [[cell cycle]] [[cell cycle checkpoint|checkpoints]] are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the [[G1 phase|G1]]/[[S phase|S]] and [[G2 phase|G2]]/[[mitosis|M]] boundaries. An intra-[[S phase|S]] checkpoint also exists. Checkpoint activation is controlled by two master [[kinase]]s, [[ataxia telangiectasia mutated|ATM]] and [[Ataxia Telangiectasia and Rad3 related|ATR]]. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,<ref>{{cite journal | vauthors = Bakkenist CJ, Kastan MB | s2cid = 4403303 | title = DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation | journal = Nature | volume = 421 | issue = 6922 | pages = 499–506 | date = January 2003 | pmid = 12556884 | doi = 10.1038/nature01368 | bibcode = 2003Natur.421..499B }}</ref> whereas ATR primarily responds to stalled [[replication fork]]s. These kinases [[phosphorylation|phosphorylate]] downstream targets in a [[signal transduction]] cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including [[BRCA1]], [[MDC1]], and [[53BP1]] has also been identified.<ref>{{cite book |title=DNA Repair, Genetic Instability, and Cancer |last1=Wei |first1=Qingyi | first2 = Lei | last2 = Li | first3 = David | last3 = Chen | name-list-style = vanc |year=2007 |publisher=World Scientific |isbn=978-981-270-014-8 }}{{page needed|date=December 2014}}</ref> These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.

An important downstream target of ATM and ATR is [[p53]], as it is required for inducing [[apoptosis]] following DNA damage.<ref>{{cite book |title=Checkpoint Controls and Cancer |url=https://archive.org/details/checkpointcontro00axel_0 |url-access=registration |last=Schonthal |first=Axel H. | name-list-style = vanc |year=2004 |publisher=Humana Press |isbn=978-1-58829-500-2 }}{{page needed|date=December 2014}}</ref> The [[cyclin-dependent kinase inhibitor]] [[p21]] is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating [[cyclin]]/[[cyclin-dependent kinase]] complexes.<ref>{{cite journal | vauthors = Gartel AL, Tyner AL | title = The role of the cyclin-dependent kinase inhibitor p21 in apoptosis | journal = Molecular Cancer Therapeutics | volume = 1 | issue = 8 | pages = 639–49 | date = June 2002 | pmid = 12479224 | url = http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12479224 }}</ref>

[[File:Dnarepair1DNA-Repair 1.png|framethumb|360px|DNA repair rate is an important determinant of cell pathology.]]

Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence.<ref name="nDNA"/> For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get [[lymphoma]] and infections more often, and, as a consequence, have shorter lifespans than wild-type mice.<ref name="espejel">{{cite journal | vauthors = Espejel S, Martín M, Klatt P, Martín-Caballero J, Flores JM, Blasco MA | title = Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice | journal = EMBO Reports | volume = 5 | issue = 5 | pages = 503–09 | date = May 2004 | pmid = 15105825 | pmc = 1299048 | doi = 10.1038/sj.embor.7400127 }}</ref> In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.<ref name="deboer">{{cite journal | vauthors = de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H, Weeda G, van der Horst GT, van Leeuwen W, Themmen AP, Meradji M, Hoeijmakers JH | s2cid = 41930529 | display-authors = 6 | title = Premature aging in mice deficient in DNA repair and transcription | journal = Science | volume = 296 | issue = 5571 | pages = 1276–79 | date = May 2002 | pmid = 11950998 | doi = 10.1126/science.1070174 | bibcode = 2002Sci...296.1276D | doi-access = free }}</ref> However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation.<ref name="dolle">{{cite journal | vauthors = Dollé ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J | display-authors = 6 | title = Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice | journal = Mutation Research | volume = 596 | issue = 1–2 | pages = 22–35 | date = April 2006 | pmid = 16472827 | doi = 10.1016/j.mrfmmm.2005.11.008 | bibcode = 2006MRFMM.596...22D }}</ref>

A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organism's diet. [[Caloric restriction]] reproducibly results in extended lifespan in a variety of organisms, likely via [[nutrient sensing]] pathways and decreased [[metabolic rate]]. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see<ref name="spindler">{{cite journal | vauthors = Spindler SR | s2cid = 7067036 | title = Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction | journal = Mechanisms of Ageing and Development | volume = 126 | issue = 9 | pages = 960–66 | date = September 2005 | pmid = 15927235 | doi = 10.1016/j.mad.2005.03.016 }}</ref> for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction. Several agents reported to have anti-aging properties have been shown to attenuate constitutive level of [[mTOR]] signaling, an evidence of reduction of [[metabolic activity]], and concurrently to reduce constitutive level of [[DNA damage]] induced by endogenously generated reactive oxygen species.<ref>{{cite journal | vauthors = Halicka HD, Zhao H, Li J, Lee YS, Hsieh TC, Wu JM, Darzynkiewicz Z | title = Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling | journal = Aging | volume = 4 | issue = 12 | pages = 952–65 | date = December 2012 | pmid = 23363784 | pmc = 3615161 | doi = 10.18632/aging.100521 }}</ref>

For example, increasing the [[gene dosage]] of the gene SIR-2, which regulates DNA packaging in the nematode worm ''[[Caenorhabditis elegans]]'', can significantly extend lifespan.<ref name="tissenbaum">{{cite journal | vauthors = Tissenbaum HA, Guarente L | s2cid = 4356885 | title = Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans | journal = Nature | volume = 410 | issue = 6825 | pages = 227–30 | date = March 2001 | pmid = 11242085 | doi = 10.1038/35065638 | bibcode = 2001Natur.410..227T }}</ref> The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.<ref name="cohen">{{cite journal | vauthors = Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA | s2cid = 33503081 | display-authors = 6 | title = Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase | journal = Science | volume = 305 | issue = 5682 | pages = 390–92 | date = July 2004 | pmid = 15205477 | doi = 10.1126/science.1099196 | bibcode = 2004Sci...305..390C }}</ref> Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,<ref name="cabelof">{{cite journal | vauthors = Cabelof DC, Yanamadala S, Raffoul JJ, Guo Z, Soofi A, Heydari AR | title = Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline | journal = DNA Repair | volume = 2 | issue = 3 | pages = 295–307 | date = March 2003 | pmid = 12547392 | doi = 10.1016/S1568-7864(02)00219-7 }}</ref> although similar effects have not been observed in mitochondrial DNA.<ref name="stuart">{{cite journal | vauthors = Stuart JA, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA | title = Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction | journal = FASEB Journal | volume = 18 | issue = 3 | pages = 595–97 | date = March 2004 | pmid = 14734635 | doi = 10.1096/fj.03-0890fje | doi-access = free | s2cid = 43118901 | url = https://zenodo.org/record/1236076 }}</ref>

Perhaps the most well-known of these 'synthetic lethality' drugs is the poly(ADP-ribose) polymerase 1 ([[PARP1]]) inhibitor [[olaparib]], which was approved by the Food and Drug Administration in 2015 for the treatment in women of BRCA-defective ovarian cancer. Tumor cells with partial loss of DNA damage response (specifically, [[homologous recombination]] repair) are dependent on another mechanism – single-strand break repair – which is a mechanism consisting, in part, of the PARP1 gene product.<ref>{{cite journal | vauthors = Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T | s2cid = 4391043 | display-authors = 6 | title = Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase | journal = Nature | volume = 434 | issue = 7035 | pages = 913–17 | date = April 2005 | pmid = 15829966 | doi = 10.1038/nature03443 | bibcode = 2005Natur.434..913B }}</ref> [[Olaparib]] is combined with chemotherapeutics to inhibit single-strand break repair induced by DNA damage caused by the co-administered chemotherapy. Tumor cells relying on this residual DNA repair mechanism are unable to repair the damage and hence are not able to survive and proliferate, whereas normal cells can repair the damage with the functioning homologous recombination mechanism.

Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by [[epigenetics|epigenetic alterations]].<ref>{{cite journal | vauthors = Baylin SB, Ohm JE | s2cid = 2514545 | title = Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? | journal = Nature Reviews. Cancer | volume = 6 | issue = 2 | pages = 107–16 | date = February 2006 | pmid = 16491070 | doi = 10.1038/nrc1799 | author-link1 = Stephen B. Baylin }}</ref>

Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in [[DNA methylation]] (hypermethylation and hypomethylation) and [[histone modification]],<ref>{{cite journal | vauthors = Kanwal R, Gupta S | title = Epigenetic modifications in cancer | journal = Clinical Genetics | volume = 81 | issue = 4 | pages = 303–11 | date = April 2012 | pmid = 22082348 | pmc = 3590802 | doi = 10.1111/j.1399-0004.2011.01809.x }}</ref> changes in chromosomal architecture (caused by inappropriate expression of proteins such as [[HMGA2]] or [[HMGA1]])<ref>{{cite journal | vauthors = Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A | display-authors = 6 | title = Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma | journal = Molecular and Cellular Biology | volume = 23 | issue = 7 | pages = 2225–38 | date = April 2003 | pmid = 12640109 | pmc = 150734 | doi = 10.1128/MCB.23.7.2225-2238.2003 }}</ref> and changes caused by [[microRNA]]s. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying [[DNA sequence]]. These changes usually remain through [[cell division]]s, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).

Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.<ref name="O'Hagan">{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | date = August 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | display-authors = 6 | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}</ref>

Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a [[missense mutation]] in the DNA repair gene [[O-6-methylguanine-DNA methyltransferase|MGMT]], while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).<ref>{{cite journal | vauthors = Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I | title = O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions | journal = Gut | volume = 54 | issue = 6 | pages = 797–802 | date = June 2005 | pmid = 15888787 | pmc = 1774551 | doi = 10.1136/gut.2004.059535 }}</ref> Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.<ref>{{cite journal | vauthors = Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP | display-authors = 6 | title = MGMT promoter methylation and field defect in sporadic colorectal cancer | journal = Journal of the National Cancer Institute | volume = 97 | issue = 18 | pages = 1330–38 | date = September 2005 | pmid = 16174854 | doi = 10.1093/jnci/dji275 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Psofaki V, Kalogera C, Tzambouras N, Stephanou D, Tsianos E, Seferiadis K, Kolios G | title = Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas | journal = World Journal of Gastroenterology | volume = 16 | issue = 28 | pages = 3553–60 | date = July 2010 | pmid = 20653064 | pmc = 2909555 | doi = 10.3748/wjg.v16.i28.3553 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH | s2cid = 8069716 | display-authors = 6 | title = Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence | journal = Langenbeck's Archives of Surgery | volume = 396 | issue = 7 | pages = 1017–26 | date = October 2011 | pmid = 21706233 | doi = 10.1007/s00423-011-0812-9 }}</ref><ref>{{cite journal | vauthors = Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G, Cassingena A, Rusconi F, Esposito A, Nichelatti M, Esteller M, Siena S | display-authors = 6 | title = Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer | journal = Clinical Cancer Research | volume = 19 | issue = 8 | pages = 2265–72 | date = April 2013 | pmid = 23422094 | doi = 10.1158/1078-0432.CCR-12-3518 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mokarram P, Zamani M, Kavousipour S, Naghibalhossaini F, Irajie C, Moradi Sarabi M, Hosseini SV | s2cid = 18733871 | title = Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer | journal = Molecular Biology Reports | volume = 40 | issue = 5 | pages = 3851–57 | date = May 2013 | pmid = 23271133 | doi = 10.1007/s11033-012-2465-3 }}</ref>

Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene [[PMS2]] expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner [[MLH1]] was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).<ref>{{cite journal | vauthors = Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G | display-authors = 6 | title = Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer | journal = Gastroenterology | volume = 128 | issue = 5 | pages = 1160–71 | date = May 2005 | pmid = 15887099 | doi = 10.1053/j.gastro.2005.01.056 | doi-access = free }}</ref> In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the [[microRNA]], [[miR-155]], which down-regulates MLH1.<ref>{{cite journal | vauthors = Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM | display-authors = 6 | title = Modulation of mismatch repair and genomic stability by miR-155 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 15 | pages = 6982–87 | date = April 2010 | pmid = 20351277 | pmc = 2872463 | doi = 10.1073/pnas.1002472107 | bibcode = 2010PNAS..107.6982V | doi-access = free }}</ref>

In a further example, epigenetic defects were found in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of [[ERCC1]], [[ERCC4|XPF]] or PMS2 occur simultaneously in the majority of 49 colon cancers evaluated by Facista et al.<ref name=Facista>{{cite journal | vauthors = Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C | display-authors = 6 | title = Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer | journal = Genome Integrity | volume = 3 | issue = 1 | pages = 3 | date = April 2012 | pmid = 22494821 | pmc = 3351028 | doi = 10.1186/2041-9414-3-3 | doi-access = free }}</ref>

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes.<ref>[http://sciencepark.mdanderson.org/labs/wood/dna_repair_genes.html Human DNA Repair Genes], 15 April 2014, MD Anderson Cancer Center, University of Texas</ref> Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.{{cn|date=January 2024}}

Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Review articles,<ref name="pmid22956494">{{cite book | vauthors = Jin B, Robertson KD | title = Epigenetic Alterations in Oncogenesis | chapter = DNA Methyltransferases, DNA Damage Repair, and Cancer | series = Advances in Experimental Medicine and Biology | volume = 754 | pages = 3–29 | date = 2013 | pmid = 22956494 | pmc = 3707278 | doi = 10.1007/978-1-4419-9967-2_1 | isbn = 978-1-4419-9966-5 }}</ref> and broad experimental survey articles<ref>{{cite journal | vauthors = Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM | display-authors = 6 | title = MicroRNA-182-5p targets a network of genes involved in DNA repair | journal = RNA | volume = 19 | issue = 2 | pages = 230–42 | date = February 2013 | pmid = 23249749 | pmc = 3543090 | doi = 10.1261/rna.034926.112 }}</ref><ref>{{cite journal | vauthors = Chaisaingmongkol J, Popanda O, Warta R, Dyckhoff G, Herpel E, Geiselhart L, Claus R, Lasitschka F, Campos B, Oakes CC, Bermejo JL, Herold-Mende C, Plass C, Schmezer P | display-authors = 6 | title = Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma | journal = Oncogene | volume = 31 | issue = 49 | pages = 5108–16 | date = December 2012 | pmid = 22286769 | doi = 10.1038/onc.2011.660 | doi-access = free }}</ref> also document most of these epigenetic DNA repair deficiencies in cancers.

Cyan-highlighted genes are in the [[microhomology-mediated end joining]] (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone ''inaccurate'' repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5–25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway.<ref name="pmid16012167"/> [[Flap structure-specific endonuclease 1|FEN1]], the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,<ref name=Singh>{{cite journal | vauthors = Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B | display-authors = 6 | title = Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers | journal = Molecular Cancer Research | volume = 6 | issue = 11 | pages = 1710–17 | date = November 2008 | pmid = 19010819 | pmc = 2948671 | doi = 10.1158/1541-7786.MCR-08-0269 }}</ref> prostate,<ref name="pmid16879693">{{cite journal | vauthors = Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS | display-authors = 6 | title = Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score | journal = BJU International | volume = 98 | issue = 2 | pages = 445–51 | date = August 2006 | pmid = 16879693 | doi = 10.1111/j.1464-410X.2006.06224.x | s2cid = 22165252 }}</ref> stomach,<ref name="pmid15701830">{{cite journal | vauthors = Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS | display-authors = 6 | title = Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells | journal = Clinical Cancer Research | volume = 11 | issue = 2 Pt 1 | pages = 473–82 | date = January 2005 | doi = 10.1158/1078-0432.473.11.2 | pmid = 15701830 | doi-access = free }}</ref><ref name="pmid24590400">{{cite journal | vauthors = Wang K, Xie C, Chen D | title = Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis | journal = International Journal of Molecular Medicine | volume = 33 | issue = 5 | pages = 1268–74 | date = May 2014 | pmid = 24590400 | doi = 10.3892/ijmm.2014.1682 | doi-access = free }}</ref> neuroblastomas,<ref name="pmid15922863">{{cite journal | vauthors = Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A | display-authors = 6 | title = Genome-wide analysis of gene expression in neuroblastomas detected by mass screening | journal = Cancer Letters | volume = 225 | issue = 1 | pages = 111–20 | date = July 2005 | pmid = 15922863 | doi = 10.1016/j.canlet.2004.10.035 | s2cid = 44644467 | url = https://hal.archives-ouvertes.fr/hal-00157917/file/Cancer_Letters_2004.pdf }}</ref> pancreas,<ref name="pmid12651607">{{cite journal | vauthors = Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M | display-authors = 6 | title = Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays | journal = The American Journal of Pathology | volume = 162 | issue = 4 | pages = 1151–62 | date = April 2003 | pmid = 12651607 | pmc = 1851213 | doi = 10.1016/S0002-9440(10)63911-9 }}</ref> and lung.<ref name="pmid14562054">{{cite journal | vauthors = Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C, Minna JD | title = Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer | journal = Oncogene | volume = 22 | issue = 46 | pages = 7243–46 | date = October 2003 | pmid = 14562054 | doi = 10.1038/sj.onc.1206977 | doi-access = free }}</ref> PARP1 is also over-expressed when its promoter region [[ETS1|ETS]] site is [[Cancer epigenetics|epigenetically]] hypomethylated, and this contributes to progression to endometrial cancer<ref name="pmid23762867">{{cite journal | vauthors = Bi FF, Li D, Yang Q | title = Hypomethylation of ETS transcription factor binding sites and upregulation of PARP1 expression in endometrial cancer | journal = BioMed Research International | volume = 2013 | pages = 946268 | year = 2013 | pmid = 23762867 | pmc = 3666359 | doi = 10.1155/2013/946268 | doi-access = free }}</ref> and BRCA-mutated serous ovarian cancer.<ref name="pmid23442605">{{cite journal | vauthors = Bi FF, Li D, Yang Q | title = Promoter hypomethylation, especially around the E26 transformation-specific motif, and increased expression of poly (ADP-ribose) polymerase 1 in BRCA-mutated serous ovarian cancer | journal = BMC Cancer | volume = 13 | pages = 90 | date = February 2013 | pmid = 23442605 | pmc = 3599366 | doi = 10.1186/1471-2407-13-90 | doi-access = free }}</ref> Other genes in the [[Microhomology-mediated end joining|MMEJ]] pathway are also over-expressed in a number of cancers (see [[Microhomology-mediated end joining|MMEJ]] for summary), and are also shown in cyan.

=== Genome-wide distribution of DNA repair in human somatic cells ===

Differential activity of DNA repair pathways across various regions of the human genome causes mutations to be very unevenly distributed within tumor genomes.<ref>{{cite journal | vauthors = Supek F, Lehner B | title = Differential DNA mismatch repair underlies mutation rate variation across the human genome | journal = Nature | volume = 521 | issue = 7550 | pages = 81–84 | date = May 2015 | pmid = 25707793 | pmc = 4425546 | doi = 10.1038/nature14173 | bibcode = 2015Natur.521...81S }}</ref><ref name=":0Zheng-2014">{{cite journal | vauthors = Zheng CL, Wang NJ, Chung J, Moslehi H, Sanborn JZ, Hur JS, Collisson EA, Vemula SS, Naujokas A, Chiotti KE, Cheng JB, Fassihi H, Blumberg AJ, Bailey CV, Fudem GM, Mihm FG, Cunningham BB, Neuhaus IM, Liao W, Oh DH, Cleaver JE, LeBoit PE, Costello JF, Lehmann AR, Gray JW, Spellman PT, Arron ST, Huh N, Purdom E, Cho RJ | display-authors = 6 | title = Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes | journal = Cell Reports | volume = 9 | issue = 4 | pages = 1228–34 | date = November 2014 | pmid = 25456125 | pmc = 4254608 | doi = 10.1016/j.celrep.2014.10.031 }}</ref> In particular, the gene-rich, early-replicating regions of the human genome exhibit lower mutation frequencies than the gene-poor, late-replicating [[heterochromatin]]. One mechanism underlying this involves the [[histone modification]] [[H3K36me3]], which can recruit [[DNA mismatch repair|mismatch repair]] proteins,<ref>{{cite journal | vauthors = Li F, Mao G, Tong D, Huang J, Gu L, Yang W, Li GM | title = The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα | journal = Cell | volume = 153 | issue = 3 | pages = 590–600 | date = April 2013 | pmid = 23622243 | pmc = 3641580 | doi = 10.1016/j.cell.2013.03.025 }}</ref> thereby lowering mutation rates in [[H3K36me3]]-marked regions.<ref>{{cite journal | vauthors = Supek F, Lehner B | title = Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes | journal = Cell | volume = 170 | issue = 3 | pages = 534–547.e23 | date = July 2017 | pmid = 28753428 | doi = 10.1016/j.cell.2017.07.003 | doi-access = free | hdl = 10230/35343 | hdl-access = free }}</ref> Another important mechanism concerns [[nucleotide excision repair]], which can be recruited by the transcription machinery, lowering somatic mutation rates in active genes<ref name=":0Zheng-2014" /> and other open chromatin regions.<ref>{{cite journal | vauthors = Polak P, Lawrence MS, Haugen E, Stoletzki N, Stojanov P, Thurman RE, Garraway LA, Mirkin S, Getz G, Stamatoyannopoulos JA, Sunyaev SR | display-authors = 6 | title = Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair | journal = Nature Biotechnology | volume = 32 | issue = 1 | pages = 71–75 | date = January 2014 | pmid = 24336318 | pmc = 4116484 | doi = 10.1038/nbt.2778 }}</ref>

When OGG1 is present at an oxidized guanine within a methylated [[CpG site]] it recruits [[TET enzymes|TET1]] to the 8-OHdG lesion (see Figure). This allows TET1 to demethylate an adjacent methylated cytosine.<ref name="pmid27251462">{{cite journal |vauthors=Zhou X, Zhuang Z, Wang W, He L, Wu H, Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo Z |title=OGG1 is essential in oxidative stress induced DNA demethylation |journal=Cell Signal |volume=28 |issue=9 |pages=1163–1171 |date=September 2016 |pmid=27251462 |doi=10.1016/j.cellsig.2016.05.021 |url=}}</ref> Demethylation of cytosine is an epigenetic alteration.<ref name="pmid22781841">{{cite journal |vauthors=Moore LD, Le T, Fan G |title=DNA methylation and its basic function |journal=Neuropsychopharmacology |volume=38 |issue=1 |pages=23–38 |date=January 2013 |pmid=22781841 |pmc=3521964 |doi=10.1038/npp.2012.112 |url=}}</ref>

As an example, when human mammary epithelial cells were treated with H₂O₂ for six hours, 8-OHdG increased about 3.5-fold in DNA and this caused about 80% demethylation of the 5-methylcytosines in the genome.<ref name=Zhou /> Demethylation of CpGs in a gene promoter by [[TET enzymes|TET enzyme]] activity increases transcription of the gene into messenger RNA.<ref name="pmid24108092">{{cite journal |vauthors=Maeder ML, Angstman JF, Richardson ME, Linder SJ, Cascio VM, Tsai SQ, Ho QH, Sander JD, Reyon D, Bernstein BE, Costello JF, Wilkinson MF, Joung JK |title=Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins |journal=Nat. Biotechnol. |volume=31 |issue=12 |pages=1137–42 |date=December 2013 |pmid=24108092 |pmc=3858462 |doi=10.1038/nbt.2726 }}</ref> In cells treated with H₂O₂, one particular gene was examined, [[Beta-secretase 1|''BACE1'']].<ref name=Zhou /> The methylation level of the ''BACE1'' [[CpG site#CpG islands|CpG island]] was reduced (an epigenetic alteration) and this allowed about 6.5 fold increase of expression of ''BACE1'' messenger RNA.{{cn|date=January 2024}}

While six-hour incubation with H₂O₂ causes considerable demethylation of 5-mCpG sites, shorter times of H₂O₂ incubation appear to promote other epigenetic alterations. Treatment of cells with H₂O₂ for 30 minutes causes the mismatch repair protein heterodimer MSH2-MSH6 to recruit DNA methyltransferase 1 (DNMT1) to sites of some kinds of oxidative DNA damage.<ref name="pmid26186941">{{cite journal |vauthors=Ding N, Bonham EM, Hannon BE, Amick TR, Baylin SB, O'Hagan HM |title=Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage |journal=J Mol Cell Biol |volume=8 |issue=3 |pages=244–54 |date=June 2016 |pmid=26186941 |pmc=4937888 |doi=10.1093/jmcb/mjv050 |url=}}</ref> This could cause increased methylation of cytosines (epigenetic alterations) at these locations.

Jiang et al.<ref name=Jiang>{{cite journal |vauthors=Jiang Z, Lai Y, Beaver JM, Tsegay PS, Zhao ML, Horton JK, Zamora M, Rein HL, Miralles F, Shaver M, Hutcheson JD, Agoulnik I, Wilson SH, Liu Y |title=Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase β and a de novo DNA Methyltransferase |journal=Cells |volume=9 |issue=1 |date=January 2020 |page=225 |pmid=31963223 |pmc=7016758 |doi=10.3390/cells9010225 |url=|doi-access=free }}</ref> treated [[HEK 293 cells]] with agents causing oxidative DNA damage, ([[potassium bromate]] (KBrO3) or [[potassium chromate]] (K2CrO4)). [[Base excision repair]] (BER) of oxidative damage occurred with the DNA repair enzyme [[DNA polymerase|polymerase beta]] localizing to oxidized guanines. Polymerase beta is the main human polymerase in short-patch BER of oxidative DNA damage. Jiang et al.<ref name=Jiang /> also found that polymerase beta recruited the [[DNA methyltransferase]] protein DNMT3b to BER repair sites. They then evaluated the methylation pattern at the single nucleotide level in a small region of DNA including the [[promoter (genetics)|promoter]] region and the early transcription region of the [[BRCA1]] gene. Oxidative DNA damage from bromate modulated the DNA methylation pattern (caused epigenetic alterations) at CpG sites within the region of DNA studied. In untreated cells, CpGs located at −189, −134, −29, −19, +16, and +19 of the BRCA1 gene had methylated cytosines (where numbering is from the [[messenger RNA]] transcription start site, and negative numbers indicate nucleotides in the upstream [[Promoter (genetics)|promoter]] region). Bromate treatment-induced oxidation resulted in the loss of cytosine methylation at −189, −134, +16 and +19 while also leading to the formation of new methylation at the CpGs located at −80, −55, −21 and +8 after DNA repair was allowed.{{cn|date=January 2024}}

At least four articles report the recruitment of [[DNA methyltransferase|DNA methyltransferase 1 (DNMT1)]] to sites of DNA double-strand breaks.<ref name="pmid15956212">{{cite journal |vauthors=Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H |title=Recruitment of DNA methyltransferase I to DNA repair sites |journal=Proc Natl Acad Sci U S A |volume=102 |issue=25 |pages=8905–9 |date=June 2005 |pmid=15956212 |pmc=1157029 |doi=10.1073/pnas.0501034102 |bibcode=2005PNAS..102.8905M |url=|doi-access=free }}</ref><ref name=Cuozzo>{{cite journal |vauthors=Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV |title=DNA damage, homology-directed repair, and DNA methylation |journal=PLOS Genet |volume=3 |issue=7 |pages=e110 |date=July 2007 |pmid=17616978 |pmc=1913100 |doi=10.1371/journal.pgen.0030110 |url= |doi-access=free }}</ref><ref name="pmid18704159">{{cite journal |vauthors=O'Hagan HM, Mohammad HP, Baylin SB |title=Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island |journal=PLOS Genet |volume=4 |issue=8 |pages=e1000155 |date=August 2008 |pmid=18704159 |pmc=2491723 |doi=10.1371/journal.pgen.1000155 |url= |doi-access=free }}<"/ref><ref name="pmid20940144">{{cite journal |vauthors=Ha K, Lee GE, Palii SS, Brown KD, Takeda Y, Liu K, Bhalla KN, Robertson KD |title=Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery |journal=Hum Mol Genet |volume=20 |issue=1 |pages=126–40 |date=January 2011 |pmid=20940144 |pmc=3000680 |doi=10.1093/hmg/ddq451 |url=}}</ref> During [[homologous recombination|homologous recombinational repair (HR)]] of the double-strand break, the involvement of DNMT1 causes the two repaired strands of DNA to have different levels of methylated cytosines. One strand becomes frequently methylated at about 21 [[CpG site]]s downstream of the repaired double-strand break. The other DNA strand loses methylation at about six CpG sites that were previously methylated downstream of the double-strand break, as well as losing methylation at about five CpG sites that were previously methylated upstream of the double-strand break. When the chromosome is replicated, this gives rise to one daughter chromosome that is heavily methylated downstream of the previous break site and one that is unmethylated in the region both upstream and downstream of the previous break site. With respect to the gene that was broken by the double-strand break, half of the progeny cells express that gene at a high level and in the other half of the progeny cells expression of that gene is repressed. When clones of these cells were maintained for three years, the new methylation patterns were maintained over that time period.<ref name="pmid27629060">{{cite journal |vauthors=Russo G, Landi R, Pezone A, Morano A, Zuchegna C, Romano A, Muller MT, Gottesman ME, Porcellini A, Avvedimento EV |title=DNA damage and Repair Modify DNA methylation and Chromatin Domain of the Targeted Locus: Mechanism of allele methylation polymorphism |journal=Sci Rep |volume=6 |issue= |pages=33222 |date=September 2016 |pmid=27629060 |pmc=5024116 |doi=10.1038/srep33222 |bibcode=2016NatSR...633222R |url=}}</ref>

In mice with a CRISPR-mediated homology-directed recombination insertion in their genome there were a large number of increased methylations of CpG sites within the double-strand break-associated insertion.<ref name="pmid33267773">{{cite journal |vauthors=Farris MH, Texter PA, Mora AA, Wiles MV, Mac Garrigle EF, Klaus SA, Rosfjord K |title=Detection of CRISPR-mediated genome modifications through altered methylation patterns of CpG islands |journal=BMC Genomics |volume=21 |issue=1 |pages=856 |date=December 2020 |pmid=33267773 |pmc=7709351 |doi=10.1186/s12864-020-07233-2 |url= |doi-access=free }}</ref>

The [[fossil record]] indicates that single-cell life began to proliferate on the planet at some point during the [[Precambrian]] period, although exactly when recognizably modern life first emerged is unclear. [[Nucleic acid]]s became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "[[oxygen catastrophe]]") due to [[photosynthesis|photosynthetic]] organisms, as well as the presence of potentially damaging [[free radical]]s in the cell due to [[oxidative phosphorylation]], necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by [[oxidative stress]]. The mechanism by which this came about, however, is unclear.{{cn|date=January 2024}}

On some occasions, DNA damage is not repaired or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, [[mutation]]s may propagate into the genomes of the cell's progeny. Should such an event occur in a [[germ line]] cell that will eventually produce a [[gamete]], the mutation has the potential to be passed on to the organism's offspring. The rate of [[evolution]] in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change.<ref name="Maresca">{{cite journal | vauthors = Maresca B, Schwartz JH | title = Sudden origins: a general mechanism of evolution based on stress protein concentration and rapid environmental change | journal = The Anatomical Record Part B: The New Anatomist | volume = 289 | issue = 1 | pages = 38–46 | date = January 2006 | pmid = 16437551 | doi = 10.1002/ar.b.20089 | doi-access = free }}</ref> DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.{{cn|date=January 2024}}

A technology named clustered regularly interspaced short palindromic repeat (shortened to [[CRISPR]]-Cas9) was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision, by inducing DNA damage at a specific point and then altering DNA repair mechanisms to insert new genes.<ref>[http://www.cbc.ca/news/health/crispr-dna-gene-editing-1.3339346 "CRISPR gene-editing tool has scientists thrilled – but nervous"] CBC news. Author Kelly Crowe. 30 November 2015.</ref> It is cheaper, more efficient, and more precise than other technologies. With the help of CRISPR–Cas9, parts of a genome can be edited by scientists by removing, adding, or altering parts in a DNA sequence.{{cn|date=January 2024}}

== See also ==

== References ==

== External links ==

* [https://pubmed.ncbi.nlm.nih.gov/26966913/{{cite journal |vauthors=Morales ME, Derbes RS, Ade CM, Ortego JC, Stark J, Deininger PL, Roy-Engel AM |title=Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes] |journal=PLOS ONE |volume=11 |issue=3 |pages=e0151367 |date=2016 |pmid=26966913 |pmc=4788447 |doi=10.1371/journal.pone.0151367 |doi-access=free |bibcode=2016PLoSO..1151367M }}