DNA Repair - Wikipedia, The Free Encyclopedia

12/04/2016
DNArepairWikipedia,thefreeencyclopedia
DNArepair
FromWikipedia,thefreeencyclopedia
DNArepairisacollectionofprocessesbywhichacell
identifiesandcorrectsdamagetotheDNAmoleculesthat
encodeitsgenome.Inhumancells,bothnormalmetabolic
activitiesandenvironmentalfactorssuchasUVlightand
radiationcancauseDNAdamage,resultinginasmanyas1
millionindividualmolecularlesionspercellperday.[1]Many
oftheselesionscausestructuraldamagetotheDNAmolecule
andcanalteroreliminatethecell'sabilitytotranscribethe
genethattheaffectedDNAencodes.Otherlesionsinduce
potentiallyharmfulmutationsinthecell'sgenome,which
affectthesurvivalofitsdaughtercellsafteritundergoes
DNAdamageresultinginmultiplebroken
mitosis.Asaconsequence,theDNArepairprocessis
chromosomes
constantlyactiveasitrespondstodamageintheDNA
structure.Whennormalrepairprocessesfail,andwhen
cellularapoptosisdoesnotoccur,irreparableDNAdamagemayoccur,includingdoublestrandbreaksand
DNAcrosslinkages(interstrandcrosslinksorICLs).[2][3]
TherateofDNArepairisdependentonmanyfactors,includingthecelltype,theageofthecell,andthe
extracellularenvironment.AcellthathasaccumulatedalargeamountofDNAdamage,oronethatno
longereffectivelyrepairsdamageincurredtoitsDNA,canenteroneofthreepossiblestates:
1.anirreversiblestateofdormancy,knownassenescence
2.cellsuicide,alsoknownasapoptosisorprogrammedcelldeath
3.unregulatedcelldivision,whichcanleadtotheformationofatumorthatiscancerous
TheDNArepairabilityofacellisvitaltotheintegrityofitsgenomeandthustothenormalfunctionalityof
thatorganism.Manygenesthatwereinitiallyshowntoinfluencelifespanhaveturnedouttobeinvolvedin
DNAdamagerepairandprotection.[4]
The2015NobelPrizeinChemistrywasawardedtoTomasLindahl,
PaulModrich,andAzizSancarfortheirworkonthemolecular
mechanismsofDNArepairprocesses.[5][6]
Contents
1 DNAdamage
1.1 Sourcesofdamage
1.2 Typesofdamage
1.3 NuclearversusmitochondrialDNAdamage
1.4 Senescenceandapoptosis
1.5 DNAdamageandmutation
https://en.wikipedia.org/wiki/DNA_repair
PaulModrich
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1.5 DNAdamageandmutation
2 DNArepairmechanisms
2.1 Directreversal
2.2 Singlestranddamage
2.3 Doublestrandbreaks
2.4 Translesionsynthesis
3 GlobalresponsetoDNAdamage
3.1 DNAdamagecheckpoints
3.2 TheprokaryoticSOSresponse
3.3 EukaryotictranscriptionalresponsestoDNA
damage
4 DNArepairandaging
4.1 PathologicaleffectsofpoorDNArepair
4.2 Longevityandcaloricrestriction
5 MedicineandDNArepairmodulation
5.1 HereditaryDNArepairdisorders
6 DNArepairandcancer
6.1 EpigeneticDNArepairdefectsincancer
6.2 FrequenciesofepimutationsinDNArepairgenes
7 DNArepairandevolution
7.1 Rateofevolutionarychange
8 DNArepairtechnology
9 Seealso
10 References
11 Externallinks
DNAdamage
DNAdamage,duetoenvironmentalfactorsandnormalmetabolicprocessesinsidethecell,occursatarate
of10,000to1,000,000molecularlesionspercellperday.[1]Whilethisconstitutesonly0.000165%ofthe
humangenome'sapproximately6billionbases(3billionbasepairs),unrepairedlesionsincriticalgenes
(suchastumorsuppressorgenes)canimpedeacell'sabilitytocarryoutitsfunctionandappreciably
increasethelikelihoodoftumorformationandcontributetotumourheterogeneity.
ThevastmajorityofDNAdamageaffectstheprimarystructureofthedoublehelixthatis,thebases
themselvesarechemicallymodified.Thesemodificationscaninturndisruptthemolecules'regularhelical
structurebyintroducingnonnativechemicalbondsorbulkyadductsthatdonotfitinthestandarddouble
helix.UnlikeproteinsandRNA,DNAusuallylackstertiarystructureandthereforedamageordisturbance
doesnotoccuratthatlevel.DNAis,however,supercoiledandwoundaround"packaging"proteinscalled
histones(ineukaryotes),andbothsuperstructuresarevulnerabletotheeffectsofDNAdamage.
Sourcesofdamage
DNAdamagecanbesubdividedintotwomaintypes:
1.endogenousdamagesuchasattackbyreactiveoxygenspeciesproducedfromnormalmetabolic
byproducts(spontaneousmutation),especiallytheprocessofoxidativedeamination
1.alsoincludesreplicationerrors
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2.exogenousdamagecausedbyexternalagentssuchas
1.ultraviolet[UV200400nm]radiationfromthesun
2.otherradiationfrequencies,includingxraysandgammarays
3.hydrolysisorthermaldisruption
4.certainplanttoxins
5.humanmademutagenicchemicals,especiallyaromaticcompoundsthatactasDNA
intercalatingagents
6.viruses[7]
ThereplicationofdamagedDNAbeforecelldivisioncanleadtotheincorporationofwrongbasesopposite
damagedones.DaughtercellsthatinheritthesewrongbasescarrymutationsfromwhichtheoriginalDNA
sequenceisunrecoverable(exceptintherarecaseofabackmutation,forexample,throughgene
conversion).
Typesofdamage
ThereareseveraltypesofdamagetoDNAduetoendogenouscellularprocesses:
1.oxidationofbases[e.g.8oxo7,8dihydroguanine(8oxoG)]andgenerationofDNAstrand
interruptionsfromreactiveoxygenspecies,
2.alkylationofbases(usuallymethylation),suchasformationof7methylguanosine,1methyladenine,
6OMethylguanine
3.hydrolysisofbases,suchasdeamination,depurination,anddepyrimidination.
4."bulkyadductformation"(i.e.,benzo[a]pyrenediolepoxidedGadduct,aristolactamIdAadduct)
5.mismatchofbases,duetoerrorsinDNAreplication,inwhichthewrongDNAbaseisstitchedinto
placeinanewlyformingDNAstrand,oraDNAbaseisskippedoverormistakenlyinserted.
6.MonoadductdamagecausebychangeinsinglenitrogenousbaseofDNA
7.Diadductdamage
Damagecausedbyexogenousagentscomesinmanyforms.Someexamplesare:
1.UVBlightcausescrosslinkingbetweenadjacentcytosineandthyminebasescreatingpyrimidine
dimers.ThisiscalleddirectDNAdamage.
2.UVAlightcreatesmostlyfreeradicals.ThedamagecausedbyfreeradicalsiscalledindirectDNA
damage.
3.IonizingradiationsuchasthatcreatedbyradioactivedecayorincosmicrayscausesbreaksinDNA
strands.IntermediatelevelionizingradiationmayinduceirreparableDNAdamage(leadingto
replicationalandtranscriptionalerrorsneededforneoplasiaormaytriggerviralinteractions)leading
toprematureagingandcancer.
4.Thermaldisruptionatelevatedtemperatureincreasestherateofdepurination(lossofpurinebases
fromtheDNAbackbone)andsinglestrandbreaks.Forexample,hydrolyticdepurinationisseenin
thethermophilicbacteria,whichgrowinhotspringsat4080C.[8][9]Therateofdepurination(300
purineresiduespergenomepergeneration)istoohighinthesespeciestoberepairedbynormal
repairmachinery,henceapossibilityofanadaptiveresponsecannotberuledout.
5.Industrialchemicalssuchasvinylchlorideandhydrogenperoxide,andenvironmentalchemicals
suchaspolycyclicaromatichydrocarbonsfoundinsmoke,sootandtarcreateahugediversityof
DNAadductsethenobases,oxidizedbases,alkylatedphosphotriestersandcrosslinkingofDNA,just
tonameafew.
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UVdamage,alkylation/methylation,Xraydamageandoxidativedamageareexamplesofinduceddamage.
Spontaneousdamagecanincludethelossofabase,deamination,sugarringpuckeringandtautomericshift.
NuclearversusmitochondrialDNAdamage
Inhumancells,andeukaryoticcellsingeneral,DNAisfoundintwocellularlocationsinsidethe
nucleusandinsidethemitochondria.NuclearDNA(nDNA)existsaschromatinduringnonreplicative
stagesofthecellcycleandiscondensedintoaggregatestructuresknownaschromosomesduringcell
division.IneitherstatetheDNAishighlycompactedandwounduparoundbeadlikeproteinscalled
histones.WheneveracellneedstoexpressthegeneticinformationencodedinitsnDNAtherequired
chromosomalregionisunravelled,geneslocatedthereinareexpressed,andthentheregioniscondensed
backtoitsrestingconformation.MitochondrialDNA(mtDNA)islocatedinsidemitochondriaorganelles,
existsinmultiplecopies,andisalsotightlyassociatedwithanumberofproteinstoformacomplexknown
asthenucleoid.Insidemitochondria,reactiveoxygenspecies(ROS),orfreeradicals,byproductsofthe
constantproductionofadenosinetriphosphate(ATP)viaoxidativephosphorylation,createahighly
oxidativeenvironmentthatisknowntodamagemtDNA.Acriticalenzymeincounteractingthetoxicityof
thesespeciesissuperoxidedismutase,whichispresentinboththemitochondriaandcytoplasmof
eukaryoticcells.
Senescenceandapoptosis
Senescence,anirreversibleprocessinwhichthecellnolongerdivides,isaprotectiveresponsetothe
shorteningofthechromosomeends.ThetelomeresarelongregionsofrepetitivenoncodingDNAthatcap
chromosomesandundergopartialdegradationeachtimeacellundergoesdivision(seeHayflicklimit).[10]
Incontrast,quiescenceisareversiblestateofcellulardormancythatisunrelatedtogenomedamage(see
cellcycle).Senescenceincellsmayserveasafunctionalalternativetoapoptosisincaseswherethe
physicalpresenceofacellforspatialreasonsisrequiredbytheorganism,[11]whichservesasa"lastresort"
mechanismtopreventacellwithdamagedDNAfromreplicatinginappropriatelyintheabsenceofpro
growthcellularsignaling.Unregulatedcelldivisioncanleadtotheformationofatumor(seecancer),which
ispotentiallylethaltoanorganism.Therefore,theinductionofsenescenceandapoptosisisconsideredtobe
partofastrategyofprotectionagainstcancer.[12]
DNAdamageandmutation
ItisimportanttodistinguishbetweenDNAdamageandmutation,thetwomajortypesoferrorinDNA.
DNAdamagesandmutationarefundamentallydifferent.DamagesarephysicalabnormalitiesintheDNA,
suchassingleanddoublestrandbreaks,8hydroxydeoxyguanosineresidues,andpolycyclicaromatic
hydrocarbonadducts.DNAdamagescanberecognizedbyenzymes,and,thus,theycanbecorrectly
repairedifredundantinformation,suchastheundamagedsequenceinthecomplementaryDNAstrandorin
ahomologouschromosome,isavailableforcopying.IfacellretainsDNAdamage,transcriptionofagene
canbeprevented,and,thus,translationintoaproteinwillalsobeblocked.Replicationmayalsobeblocked
orthecellmaydie.
IncontrasttoDNAdamage,amutationisachangeinthebasesequenceoftheDNA.Amutationcannotbe
recognizedbyenzymesoncethebasechangeispresentinbothDNAstrands,and,thus,amutationcannot
berepaired.Atthecellularlevel,mutationscancausealterationsinproteinfunctionandregulation.
Mutationsarereplicatedwhenthecellreplicates.Inapopulationofcells,mutantcellswillincreaseor
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decreaseinfrequencyaccordingtotheeffectsofthemutationontheabilityofthecelltosurviveand
reproduce.Althoughdistinctlydifferentfromeachother,DNAdamagesandmutationsarerelatedbecause
DNAdamagesoftencauseerrorsofDNAsynthesisduringreplicationorrepairtheseerrorsareamajor
sourceofmutation.
GiventhesepropertiesofDNAdamageandmutation,itcanbeseenthatDNAdamagesareaspecial
probleminnondividingorslowlydividingcells,whereunrepaireddamageswilltendtoaccumulateover
time.Ontheotherhand,inrapidlydividingcells,unrepairedDNAdamagesthatdonotkillthecellby
blockingreplicationwilltendtocausereplicationerrorsandthusmutation.Thegreatmajorityofmutations
thatarenotneutralintheireffectaredeleterioustoacell'ssurvival.Thus,inapopulationofcells
composingatissuewithreplicatingcells,mutantcellswilltendtobelost.However,infrequentmutations
thatprovideasurvivaladvantagewilltendtoclonallyexpandattheexpenseofneighboringcellsinthe
tissue.Thisadvantagetothecellisdisadvantageoustothewholeorganism,becausesuchmutantcellscan
giverisetocancer.Thus,DNAdamagesinfrequentlydividingcells,becausetheygiverisetomutations,
areaprominentcauseofcancer.Incontrast,DNAdamagesininfrequentlydividingcellsarelikelya
prominentcauseofaging.[13]
DNArepairmechanisms
CellscannotfunctionifDNAdamagecorruptstheintegrityandaccessibilityof
essentialinformationinthegenome(butcellsremainsuperficiallyfunctional
whennonessentialgenesaremissingordamaged).Dependingonthetypeof
damageinflictedontheDNA'sdoublehelicalstructure,avarietyofrepair
strategieshaveevolvedtorestorelostinformation.Ifpossible,cellsusethe
unmodifiedcomplementarystrandoftheDNAorthesisterchromatidasa
templatetorecovertheoriginalinformation.Withoutaccesstoatemplate,cells
useanerrorpronerecoverymechanismknownastranslesionsynthesisasalast
resort.
DamagetoDNAaltersthespatialconfigurationofthehelix,andsuch
alterationscanbedetectedbythecell.Oncedamageislocalized,specificDNA
repairmoleculesbindatornearthesiteofdamage,inducingothermoleculesto
bindandformacomplexthatenablestheactualrepairtotakeplace.
Directreversal
CellsareknowntoeliminatethreetypesofdamagetotheirDNAbychemically
reversingit.Thesemechanismsdonotrequireatemplate,sincethetypesof
damagetheycounteractcanoccurinonlyoneofthefourbases.Suchdirect
reversalmechanismsarespecifictothetypeofdamageincurredanddonot
involvebreakageofthephosphodiesterbackbone.Theformationofpyrimidine
dimersuponirradiationwithUVlightresultsinanabnormalcovalentbond
betweenadjacentpyrimidinebases.Thephotoreactivationprocessdirectly
reversesthisdamagebytheactionoftheenzymephotolyase,whoseactivation
isobligatelydependentonenergyabsorbedfromblue/UVlight(300500nm
wavelength)topromotecatalysis.[14]Photolyase,anoldenzymepresentin
bacteria,fungi,andmostanimalsnolongerfunctionsinhumans,[15]who
Singlestrandand
doublestrandDNA
damage
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insteadusenucleotideexcisionrepairtorepairdamagefromUVirradiation.Anothertypeofdamage,
methylationofguaninebases,isdirectlyreversedbytheproteinmethylguaninemethyltransferase
(MGMT),thebacterialequivalentofwhichiscalledogt.ThisisanexpensiveprocessbecauseeachMGMT
moleculecanbeusedonlyoncethatis,thereactionisstoichiometricratherthancatalytic.[16]Ageneralized
responsetomethylatingagentsinbacteriaisknownastheadaptiveresponseandconfersalevelof
resistancetoalkylatingagentsuponsustainedexposurebyupregulationofalkylationrepairenzymes.[17]
ThethirdtypeofDNAdamagereversedbycellsiscertainmethylationofthebasescytosineandadenine.
Singlestranddamage
Whenonlyoneofthetwostrandsofadoublehelixhasa
defect,theotherstrandcanbeusedasatemplatetoguidethe
correctionofthedamagedstrand.Inordertorepairdamageto
oneofthetwopairedmoleculesofDNA,thereexistanumber
ofexcisionrepairmechanismsthatremovethedamaged
nucleotideandreplaceitwithanundamagednucleotide
complementarytothatfoundintheundamagedDNAstrand.[16]
1.Baseexcisionrepair(BER)repairsdamagetoasingle
nitrogenousbasebydeployingenzymescalledglycosylases.[18]
Theseenzymesremoveasinglenitrogenousbasetocreatean
Structureofthebaseexcisionrepair
apurinicorapyrimidinicsite(APsite).[18]EnzymescalledAP
enzymeuracilDNAglycosylase.The
endonucleasesnickthedamagedDNAbackboneattheAPsite.
uracilresidueisshowninyellow.
DNApolymerasethenremovesthedamagedregionusingits5
to3exonucleaseactivityandcorrectlysynthesizesthenew
strandusingthecomplementarystrandasatemplate.[18]
2.Nucleotideexcisionrepair(NER)repairsdamagedDNAwhichcommonlyconsistsofbulky,helix
distortingdamage,suchaspyrimidinedimerizationcausedbyUVlight.Damagedregionsare
removedin1224nucleotidelongstrandsinathreestepprocesswhichconsistsofrecognitionof
damage,excisionofdamagedDNAbothupstreamanddownstreamofdamagebyendonucleases,and
resynthesisofremovedDNAregion.[19]NERisahighlyevolutionarilyconservedrepairmechanism
andisusedinnearlyalleukaryoticandprokaryoticcells.[19]Inprokaryotes,NERismediatedbyUvr
proteins.[19]Ineukaryotes,manymoreproteinsareinvolved,althoughthegeneralstrategyisthe
same.[19]
3.Mismatchrepairsystemsarepresentinessentiallyallcellstocorrecterrorsthatarenotcorrectedby
proofreading.Thesesystemsconsistofatleasttwoproteins.Onedetectsthemismatch,andtheother
recruitsanendonucleasethatcleavesthenewlysynthesizedDNAstrandclosetotheregionof
damage.InE.coli,theproteinsinvolvedaretheMutclassproteins.Thisisfollowedbyremovalof
damagedregionbyanexonuclease,resynthesisbyDNApolymerase,andnicksealingbyDNA
ligase.[20]
Doublestrandbreaks
Doublestrandbreaks,inwhichbothstrandsinthedoublehelixaresevered,areparticularlyhazardousto
thecellbecausetheycanleadtogenomerearrangements.Threemechanismsexisttorepairdoublestrand
breaks(DSBs):nonhomologousendjoining(NHEJ),microhomologymediatedendjoining(MMEJ),and
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homologousrecombination.[16]PVNAcharyanotedthatdoublestrandbreaksanda"crosslinkagejoining
bothstrandsatthesamepointisirreparablebecauseneitherstrandcanthenserveasatemplateforrepair.
Thecellwilldieinthenextmitosisorinsomerareinstances,mutate."[2][3]
InNHEJ,DNALigaseIV,aspecializedDNAligasethatformsa
complexwiththecofactorXRCC4,directlyjoinsthetwoends.[21]
Toguideaccuraterepair,NHEJreliesonshorthomologous
sequencescalledmicrohomologiespresentonthesinglestranded
tailsoftheDNAendstobejoined.Iftheseoverhangsare
compatible,repairisusuallyaccurate.[22][23][24][25]NHEJcanalso
introducemutationsduringrepair.Lossofdamagednucleotidesat
thebreaksitecanleadtodeletions,andjoiningofnonmatching
terminiformsinsertionsortranslocations.NHEJisespecially
importantbeforethecellhasreplicateditsDNA,sincethereisno
templateavailableforrepairbyhomologousrecombination.There
are"backup"NHEJpathwaysinhighereukaryotes.[26]Besidesits
roleasagenomecaretaker,NHEJisrequiredforjoininghairpin
cappeddoublestrandbreaksinducedduringV(D)Jrecombination,
theprocessthatgeneratesdiversityinBcellandTcellreceptorsin
thevertebrateimmunesystem.[27]
MMEJstartswithshortrangeendresectionbyMRE11nuclease
oneithersideofadoublestrandbreaktorevealmicrohomology
regions.[28]Infurthersteps,[29]PARP1isrequiredandmaybean
earlystepinMMEJ.Thereispairingofmicrohomologyregions
followedbyrecruitmentofflapstructurespecificendonuclease1
(FEN1)toremoveoverhangingflaps.Thisisfollowedby
recruitmentofXRCC1LIG3tothesiteforligatingtheDNAends,
leadingtoanintactDNA.
DNAligase,shownaboverepairing
chromosomaldamage,isanenzyme
thatjoinsbrokennucleotidestogether
bycatalyzingtheformationofan
internucleotideesterbondbetweenthe
phosphatebackboneandthe
deoxyribosenucleotides.
DNAdoublestrandbreaksinmammaliancellsareprimarilyrepairedbyhomologousrecombination(HR)
andnonhomologousendjoining(NHEJ).[30]Inaninvitrosystem,MMEJoccurredinmammaliancellsat
thelevelsof1020%ofHRwhenbothHRandNHEJmechanismswerealsoavailable.[28]MMEJisalways
accompaniedbyadeletion,sothatMMEJisamutagenicpathwayforDNArepair.[31]
Homologousrecombinationrequiresthepresenceofanidenticalornearlyidenticalsequencetobeusedas
atemplateforrepairofthebreak.Theenzymaticmachineryresponsibleforthisrepairprocessisnearly
identicaltothemachineryresponsibleforchromosomalcrossoverduringmeiosis.Thispathwayallowsa
damagedchromosometoberepairedusingasisterchromatid(availableinG2afterDNAreplication)ora
homologouschromosomeasatemplate.DSBscausedbythereplicationmachineryattemptingto
synthesizeacrossasinglestrandbreakorunrepairedlesioncausecollapseofthereplicationforkandare
typicallyrepairedbyrecombination.
TopoisomerasesintroducebothsingleanddoublestrandbreaksinthecourseofchangingtheDNA'sstate
ofsupercoiling,whichisespeciallycommoninregionsnearanopenreplicationfork.Suchbreaksarenot
consideredDNAdamagebecausetheyareanaturalintermediateinthetopoisomerasebiochemical
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mechanismandareimmediatelyrepairedbytheenzymesthatcreatedthem.
AteamofFrenchresearchersbombardedDeinococcusradioduranstostudythemechanismofdouble
strandbreakDNArepairinthatorganism.Atleasttwocopiesofthegenome,withrandomDNAbreaks,
canformDNAfragmentsthroughannealing.Partiallyoverlappingfragmentsarethenusedforsynthesisof
homologousregionsthroughamovingDloopthatcancontinueextensionuntiltheyfindcomplementary
partnerstrands.InthefinalstepthereiscrossoverbymeansofRecAdependenthomologous
recombination.[32]
Translesionsynthesis
Translesionsynthesis(TLS)isaDNAdamagetoleranceprocessthatallowstheDNAreplicationmachinery
toreplicatepastDNAlesionssuchasthyminedimersorAPsites.[33]ItinvolvesswitchingoutregularDNA
polymerasesforspecializedtranslesionpolymerases(i.e.DNApolymeraseIVorV,fromtheYPolymerase
family),oftenwithlargeractivesitesthatcanfacilitatetheinsertionofbasesoppositedamagednucleotides.
Thepolymeraseswitchingisthoughttobemediatedby,amongotherfactors,theposttranslational
modificationofthereplicationprocessivityfactorPCNA.Translesionsynthesispolymerasesoftenhavelow
fidelity(highpropensitytoinsertwrongbases)onundamagedtemplatesrelativetoregularpolymerases.
However,manyareextremelyefficientatinsertingcorrectbasesoppositespecifictypesofdamage.For
example,PolmediateserrorfreebypassoflesionsinducedbyUVirradiation,whereasPolintroduces
mutationsatthesesites.PolisknowntoaddthefirstadenineacrosstheT^TphotodimerusingWatson
CrickbasepairingandthesecondadeninewillbeaddedinitssynconformationusingHoogsteenbase
pairing.Fromacellularperspective,riskingtheintroductionofpointmutationsduringtranslesionsynthesis
maybepreferabletoresortingtomoredrasticmechanismsofDNArepair,whichmaycausegross
chromosomalaberrationsorcelldeath.Inshort,theprocessinvolvesspecializedpolymeraseseither
bypassingorrepairinglesionsatlocationsofstalledDNAreplication.Forexample,HumanDNA
polymeraseetacanbypasscomplexDNAlesionslikeguaninethymineintrastrandcrosslink,G[8,5Me]T,
althoughcancausetargetedandsemitargetedmutations.[34]ParomitaRaychaudhuryandAshisBasu[35]
studiedthetoxicityandmutagenesisofthesamelesioninEscherichiacolibyreplicatingaG[8,5Me]T
modifiedplasmidinE.coliwithspecificDNApolymeraseknockouts.Viabilitywasverylowinastrain
lackingpolII,polIV,andpolV,thethreeSOSinducibleDNApolymerases,indicatingthattranslesion
synthesisisconductedprimarilybythesespecializedDNApolymerases.Abypassplatformisprovidedto
thesepolymerasesbyProliferatingcellnuclearantigen(PCNA).Undernormalcircumstances,PCNA
boundtopolymerasesreplicatestheDNA.Atasiteoflesion,PCNAisubiquitinated,ormodified,bythe
RAD6/RAD18proteinstoprovideaplatformforthespecializedpolymerasestobypassthelesionand
resumeDNAreplication.[36][37]Aftertranslesionsynthesis,extensionisrequired.Thisextensioncanbe
carriedoutbyareplicativepolymeraseiftheTLSiserrorfree,asinthecaseofPol,yetifTLSresultsin
amismatch,aspecializedpolymeraseisneededtoextenditPol.Polisuniqueinthatitcanextend
terminalmismatches,whereasmoreprocessivepolymerasescannot.Sowhenalesionisencountered,the
replicationforkwillstall,PCNAwillswitchfromaprocessivepolymerasetoaTLSpolymerasesuchas
Poltofixthelesion,thenPCNAmayswitchtoPoltoextendthemismatch,andlastPCNAwillswitch
totheprocessivepolymerasetocontinuereplication.
GlobalresponsetoDNAdamage
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Cellsexposedtoionizingradiation,ultravioletlightorchemicalsarepronetoacquiremultiplesitesof
bulkyDNAlesionsanddoublestrandbreaks.Moreover,DNAdamagingagentscandamageother
biomoleculessuchasproteins,carbohydrates,lipids,andRNA.Theaccumulationofdamage,tobe
specific,doublestrandbreaksoradductsstallingthereplicationforks,areamongknownstimulationsignals
foraglobalresponsetoDNAdamage.[38]Theglobalresponsetodamageisanactdirectedtowardthecells'
ownpreservationandtriggersmultiplepathwaysofmacromolecularrepair,lesionbypass,tolerance,or
apoptosis.Thecommonfeaturesofglobalresponseareinductionofmultiplegenes,cellcyclearrest,and
inhibitionofcelldivision.
DNAdamagecheckpoints
AfterDNAdamage,cellcyclecheckpointsareactivated.Checkpointactivationpausesthecellcycleand
givesthecelltimetorepairthedamagebeforecontinuingtodivide.DNAdamagecheckpointsoccuratthe
G1/SandG2/Mboundaries.AnintraScheckpointalsoexists.Checkpointactivationiscontrolledbytwo
masterkinases,ATMandATR.ATMrespondstoDNAdoublestrandbreaksanddisruptionsinchromatin
structure,[39]whereasATRprimarilyrespondstostalledreplicationforks.Thesekinasesphosphorylate
downstreamtargetsinasignaltransductioncascade,eventuallyleadingtocellcyclearrest.Aclassof
checkpointmediatorproteinsincludingBRCA1,MDC1,and53BP1hasalsobeenidentified.[40]These
proteinsseemtoberequiredfortransmittingthecheckpointactivationsignaltodownstreamproteins.
DNAdamagecheckpointisasignaltransductionpathwaythatblockscellcycleprogressioninG1,G2and
metaphaseandslowsdowntherateofSphaseprogressionwhenDNAisdamaged.Itleadstoapausein
cellcycleallowingthecelltimetorepairthedamagebeforecontinuingtodivide.
CheckpointProteinscanbeseparatedintofourgroups:phosphatidylinositol3kinase(PI3K)likeprotein
kinase,proliferatingcellnuclearantigen(PCNA)likegroup,twoserine/threonine(S/T)kinasesandtheir
adaptors.CentraltoallDNAdamageinducedcheckpointsresponsesisapairoflargeproteinkinases
belongingtothefirstgroupofPI3KlikeproteinkinasestheATM(Ataxiatelangiectasiamutated)andATR
(AtaxiaandRadrelated)kinases,whosesequenceandfunctionshavebeenwellconservedinevolution.
AllDNAdamageresponserequireseitherATMorATRbecausetheyhavetheabilitytobindtothe
chromosomesatthesiteofDNAdamage,togetherwithaccessoryproteinsthatareplatformsonwhich
DNAdamageresponsecomponentsandDNArepaircomplexescanbeassembled.
AnimportantdownstreamtargetofATMandATRisp53,asitisrequiredforinducingapoptosisfollowing
DNAdamage.[41]Thecyclindependentkinaseinhibitorp21isinducedbybothp53dependentandp53
independentmechanismsandcanarrestthecellcycleattheG1/SandG2/Mcheckpointsbydeactivating
cyclin/cyclindependentkinasecomplexes.[42]
TheprokaryoticSOSresponse
TheSOSresponseisthechangesingeneexpressioninEscherichiacoliandotherbacteriainresponseto
extensiveDNAdamage.TheprokaryoticSOSsystemisregulatedbytwokeyproteins:LexAandRecA.
TheLexAhomodimerisatranscriptionalrepressorthatbindstooperatorsequencescommonlyreferredto
asSOSboxes.InEscherichiacoliitisknownthatLexAregulatestranscriptionofapproximately48genes
includingthelexAandrecAgenes.[43]TheSOSresponseisknowntobewidespreadintheBacteria
domain,butitismostlyabsentinsomebacterialphyla,liketheSpirochetes.[44]Themostcommoncellular
signalsactivatingtheSOSresponseareregionsofsinglestrandedDNA(ssDNA),arisingfromstalled
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replicationforksordoublestrandbreaks,whichareprocessedbyDNAhelicasetoseparatethetwoDNA
strands.[38]Intheinitiationstep,RecAproteinbindstossDNAinanATPhydrolysisdrivenreaction
creatingRecAssDNAfilaments.RecAssDNAfilamentsactivateLexAautoproteaseactivity,which
ultimatelyleadstocleavageofLexAdimerandsubsequentLexAdegradation.ThelossofLexArepressor
inducestranscriptionoftheSOSgenesandallowsforfurthersignalinduction,inhibitionofcelldivision
andanincreaseinlevelsofproteinsresponsiblefordamageprocessing.
InEscherichiacoli,SOSboxesare20nucleotidelongsequencesnearpromoterswithpalindromicstructure
andahighdegreeofsequenceconservation.Inotherclassesandphyla,thesequenceofSOSboxesvaries
considerably,withdifferentlengthandcomposition,butitisalwayshighlyconservedandoneofthe
strongestshortsignalsinthegenome.[44]ThehighinformationcontentofSOSboxespermitsdifferential
bindingofLexAtodifferentpromotersandallowsfortimingoftheSOSresponse.Thelesionrepairgenes
areinducedatthebeginningofSOSresponse.Theerrorpronetranslesionpolymerases,forexample,
UmuCD'2(alsocalledDNApolymeraseV),areinducedlateronasalastresort.[45]OncetheDNAdamage
isrepairedorbypassedusingpolymerasesorthroughrecombination,theamountofsinglestrandedDNAin
cellsisdecreased,loweringtheamountsofRecAfilamentsdecreasescleavageactivityofLexA
homodimer,whichthenbindstotheSOSboxesnearpromotersandrestoresnormalgeneexpression.
EukaryotictranscriptionalresponsestoDNAdamage
EukaryoticcellsexposedtoDNAdamagingagentsalsoactivateimportantdefensivepathwaysbyinducing
multipleproteinsinvolvedinDNArepair,cellcyclecheckpointcontrol,proteintraffickinganddegradation.
Suchgenomewidetranscriptionalresponseisverycomplexandtightlyregulated,thusallowing
coordinatedglobalresponsetodamage.ExposureofyeastSaccharomycescerevisiaetoDNAdamaging
agentsresultsinoverlappingbutdistincttranscriptionalprofiles.Similaritiestoenvironmentalshock
responseindicatesthatageneralglobalstressresponsepathwayexistattheleveloftranscriptional
activation.Incontrast,differenthumancelltypesrespondtodamagedifferentlyindicatinganabsenceofa
commonglobalresponse.Theprobableexplanationforthisdifferencebetweenyeastandhumancellsmay
beintheheterogeneityofmammaliancells.Inananimaldifferenttypesofcellsaredistributedamong
differentorgansthathaveevolveddifferentsensitivitiestoDNAdamage.[46]
IngeneralglobalresponsetoDNAdamageinvolvesexpressionofmultiplegenesresponsiblefor
postreplicationrepair,homologousrecombination,nucleotideexcisionrepair,DNAdamagecheckpoint,
globaltranscriptionalactivation,genescontrollingmRNAdecay,andmanyothers.Alargeamountof
damagetoacellleavesitwithanimportantdecision:undergoapoptosisanddie,orsurviveatthecostof
livingwithamodifiedgenome.Anincreaseintolerancetodamagecanleadtoanincreasedrateofsurvival
thatwillallowagreateraccumulationofmutations.YeastRev1andhumanpolymerasearemembersof
[YfamilytranslesionDNApolymerasespresentduringglobalresponsetoDNAdamageandare
responsibleforenhancedmutagenesisduringaglobalresponsetoDNAdamageineukaryotes.[38]
DNArepairandaging
PathologicaleffectsofpoorDNArepair
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Experimentalanimalswithgenetic
deficienciesinDNArepairoften
showdecreasedlifespanand
increasedcancerincidence.[13]For
example,micedeficientinthe
dominantNHEJpathwayandin
telomeremaintenancemechanisms
getlymphomaandinfectionsmore
often,and,asaconsequence,have
shorterlifespansthanwildtype
mice.[47]Insimilarmanner,mice
deficientinakeyrepairand
transcriptionproteinthatunwinds
DNAheliceshaveprematureonset
ofagingrelateddiseasesand
consequentshorteningof
DNArepairrateisanimportantdeterminantofcellpathology
lifespan.[48]However,notevery
DNArepairdeficiencycreates
exactlythepredictedeffectsmice
deficientintheNERpathwayexhibitedshortenedlifespanwithoutcorrespondinglyhigherratesof
mutation.[49]
IftherateofDNAdamageexceedsthecapacityofthecelltorepairit,theaccumulationoferrorscan
overwhelmthecellandresultinearlysenescence,apoptosis,orcancer.Inheriteddiseasesassociatedwith
faultyDNArepairfunctioningresultinprematureaging,[13]increasedsensitivitytocarcinogens,and
correspondinglyincreasedcancerrisk(seebelow).Ontheotherhand,organismswithenhancedDNA
repairsystems,suchasDeinococcusradiodurans,themostradiationresistantknownorganism,exhibit
remarkableresistancetothedoublestrandbreakinducingeffectsofradioactivity,likelyduetoenhanced
efficiencyofDNArepairandespeciallyNHEJ.[50]
Longevityandcaloricrestriction
Anumberofindividualgeneshavebeenidentifiedasinfluencingvariationsinlifespanwithinapopulation
oforganisms.Theeffectsofthesegenesisstronglydependentontheenvironment,inparticular,onthe
organism'sdiet.Caloricrestrictionreproduciblyresultsinextendedlifespaninavarietyoforganisms,likely
vianutrientsensingpathwaysanddecreasedmetabolicrate.Themolecularmechanismsbywhichsuch
restrictionresultsinlengthenedlifespanareasyetunclear(see[51]forsomediscussion)however,the
behaviorofmanygenesknowntobeinvolvedinDNArepairisalteredunderconditionsofcaloric
restriction.
Forexample,increasingthegenedosageofthegeneSIR2,whichregulatesDNApackaginginthe
nematodewormCaenorhabditiselegans,cansignificantlyextendlifespan.[52]Themammalianhomologof
SIR2isknowntoinducedownstreamDNArepairfactorsinvolvedinNHEJ,anactivitythatisespecially
promotedunderconditionsofcaloricrestriction.[53]Caloricrestrictionhasbeencloselylinkedtotherateof
baseexcisionrepairinthenuclearDNAofrodents,[54]althoughsimilareffectshavenotbeenobservedin
mitochondrialDNA.[55]
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ItisinterestingtonotethattheC.
elegansgeneAGE1,anupstream
effectorofDNArepairpathways,
confersdramaticallyextendedlifespan
underfreefeedingconditionsbutleads
toadecreaseinreproductivefitness
underconditionsofcaloric
restriction.[56]Thisobservationsupports
thepleiotropytheoryofthebiological
originsofaging,whichsuggeststhat
genesconferringalargesurvival
advantageearlyinlifewillbeselected
foreveniftheycarryacorresponding
disadvantagelateinlife.
MedicineandDNA
repairmodulation
HereditaryDNArepair
disorders
DefectsintheNERmechanismare
responsibleforseveralgenetic
disorders,including:
Xerodermapigmentosum:
hypersensitivitytosunlight/UV,
MostlifespaninfluencinggenesaffecttherateofDNAdamage
resultinginincreasedskincancer
incidenceandprematureaging
Cockaynesyndrome:hypersensitivitytoUVandchemicalagents
Trichothiodystrophy:sensitiveskin,brittlehairandnails
Mentalretardationoftenaccompaniesthelattertwodisorders,suggestingincreasedvulnerabilityof
developmentalneurons.
OtherDNArepairdisordersinclude:
Werner'ssyndrome:prematureagingandretardedgrowth
Bloom'ssyndrome:sunlighthypersensitivity,highincidenceofmalignancies(especiallyleukemias).
Ataxiatelangiectasia:sensitivitytoionizingradiationandsomechemicalagents
Alloftheabovediseasesareoftencalled"segmentalprogerias"("acceleratedagingdiseases")becausetheir
victimsappearelderlyandsufferfromagingrelateddiseasesatanabnormallyyoungage,whilenot
manifestingallthesymptomsofoldage.
OtherdiseasesassociatedwithreducedDNArepairfunctionincludeFanconianemia,hereditarybreast
cancerandhereditarycoloncancer.
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DNArepairandcancer
BecauseofinherentlimitationsintheDNArepairmechanisms,ifhumanslivedlongenough,theywould
alleventuallydevelopcancer.[57][58]Thereareatleast34InheritedhumanDNArepairgenemutationsthat
increasecancerrisk.ManyofthesemutationscauseDNArepairtobelesseffectivethannormal.In
particular,Hereditarynonpolyposiscolorectalcancer(HNPCC)isstronglyassociatedwithspecific
mutationsintheDNAmismatchrepairpathway.BRCA1andBRCA2,twofamousgeneswhosemutations
conferahugelyincreasedriskofbreastcanceroncarriers,arebothassociatedwithalargenumberofDNA
repairpathways,especiallyNHEJandhomologousrecombination.
Cancertherapyproceduressuchaschemotherapyandradiotherapyworkbyoverwhelmingthecapacityof
thecelltorepairDNAdamage,resultingincelldeath.Cellsthataremostrapidlydividingmosttypically
cancercellsarepreferentiallyaffected.Thesideeffectisthatothernoncancerousbutrapidlydividing
cellssuchasprogenitorcellsinthegut,skin,andhematopoieticsystemarealsoaffected.Moderncancer
treatmentsattempttolocalizetheDNAdamagetocellsandtissuesonlyassociatedwithcancer,eitherby
physicalmeans(concentratingthetherapeuticagentintheregionofthetumor)orbybiochemicalmeans
(exploitingafeatureuniquetocancercellsinthebody).
EpigeneticDNArepairdefectsincancer
Classically,cancerhasbeenviewedasasetofdiseasesthataredrivenbyprogressivegeneticabnormalities
thatincludemutationsintumoursuppressorgenesandoncogenes,andchromosomalaberrations.However,
ithasbecomeapparentthatcancerisalsodrivenbyepigeneticalterations.[59]
Epigeneticalterationsrefertofunctionallyrelevantmodificationstothegenomethatdonotinvolvea
changeinthenucleotidesequence.ExamplesofsuchmodificationsarechangesinDNAmethylation
(hypermethylationandhypomethylation)andhistonemodification,[60]changesinchromosomalarchitecture
(causedbyinappropriateexpressionofproteinssuchasHMGA2orHMGA1)[61]andchangescausedby
microRNAs.Eachoftheseepigeneticalterationsservestoregulategeneexpressionwithoutalteringthe
underlyingDNAsequence.Thesechangesusuallyremainthroughcelldivisions,lastformultiplecell
generations,andcanbeconsideredtobeepimutations(equivalenttomutations).
Whilelargenumbersofepigeneticalterationsarefoundincancers,theepigeneticalterationsinDNArepair
genes,causingreducedexpressionofDNArepairproteins,appeartobeparticularlyimportant.Such
alterationsarethoughttooccurearlyinprogressiontocancerandtobealikelycauseofthegenetic
instabilitycharacteristicofcancers.[62][63][64][65]
ReducedexpressionofDNArepairgenescausesdeficientDNArepair.WhenDNArepairisdeficientDNA
damagesremainincellsatahigherthanusuallevelandtheseexcessdamagescauseincreasedfrequencies
ofmutationorepimutation.MutationratesincreasesubstantiallyincellsdefectiveinDNAmismatch
repair[66][67]orinhomologousrecombinationalrepair(HRR).[68]Chromosomalrearrangementsand
aneuploidyalsoincreaseinHRRdefectivecells.[69]
HigherlevelsofDNAdamagenotonlycauseincreasedmutation,butalsocauseincreasedepimutation.
DuringrepairofDNAdoublestrandbreaks,orrepairofotherDNAdamages,incompletelyclearedsitesof
repaircancauseepigeneticgenesilencing.[70][71]
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DeficientexpressionofDNArepairproteinsduetoaninheritedmutationcancauseincreasedriskof
cancer.Individualswithaninheritedimpairmentinanyof34DNArepairgenes(seearticleDNArepair
deficiencydisorder)haveanincreasedriskofcancer,withsomedefectscausinguptoa100%lifetime
chanceofcancer(e.g.p53mutations).[72]However,suchgermlinemutations(whichcausehighlypenetrant
cancersyndromes)arethecauseofonlyabout1percentofcancers.[73]
FrequenciesofepimutationsinDNArepairgenes
DeficienciesinDNArepairenzymesare
occasionallycausedbyanewlyarising
somaticmutationinaDNArepairgene,
butaremuchmorefrequentlycausedby
epigeneticalterationsthatreduceor
silenceexpressionofDNArepairgenes.
Forexample,when113colorectal
cancerswereexaminedinsequence,
onlyfourhadamissensemutationinthe
DNArepairgeneMGMT,whilethe
majorityhadreducedMGMT
expressionduetomethylationofthe
MGMTpromoterregion(anepigenetic
alteration).[74]Fivedifferentstudies
foundthatbetween40%and90%of
colorectalcancershavereducedMGMT
expressionduetomethylationofthe
MGMTpromoter
region.[75][76][77][78][79]
Similarly,outof119casesofmismatch
repairdeficientcolorectalcancersthat
lackedDNArepairgenePMS2
expression,PMS2wasdeficientin6
duetomutationsinthePMS2gene,
whilein103casesPMS2expression
wasdeficientbecauseitspairingpartner
MLH1wasrepressedduetopromoter
methylation(PMS2proteinisunstable
intheabsenceofMLH1).[80]Inthe
other10cases,lossofPMS2expression
waslikelyduetoepigenetic
overexpressionofthemicroRNA,miR
155,whichdownregulatesMLH1.[81]
AchartofcommonDNAdamagingagents,examplesoflesionsthey
causeinDNA,andpathwaysusedtorepairtheselesions.Alsoshown
aremanyofthegenesinthesepathways,anindicationofwhich
genesareepigeneticallyregulated,andwhichofthoseepigenetically
regulatedgeneshavereducedexpressioninvariouscancers.Italso
showsgenesintheerrorpronemicrohomologymediatedendjoining
pathwaywithincreasedexpressioninvariouscancers
Infurtherexamples(tabulatedinCancer
epigenetics),epigeneticdefectswerefoundatfrequenciesofbetween13%100%fortheDNArepairgenes
BRCA1,WRN,FANCB,FANCF,MGMT,MLH1,MSH2,MSH4,ERCC1,XPF,NEIL1andATM.These
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epigeneticdefectsoccurredinvariouscancers(e.g.breast,ovarian,colorectalandheadandneck).Twoor
threedeficienciesintheexpressionofERCC1,XPForPMS2occursimultaneouslyinthemajorityofthe
49coloncancersevaluatedbyFacistaetal.[82]
ThechartinthissectionshowssomefrequentDNAdamagingagents,examplesofDNAlesionstheycause,
andthepathwaysthatdealwiththeseDNAdamages.Atleast169enzymesareeitherdirectlyemployedin
DNArepairorinfluenceDNArepairprocesses.[83]Ofthese,83aredirectlyemployedinthe5typesof
DNArepairprocessesillustratedinthechart.Themorewellstudiedgenescentraltotheserepairprocesses
arealsoshowninthechart.AsindicatedbytheDNArepairgenesshowninred,manyofthegenesinthese
repairpathwaysareregulatedbyepigeneticmechanisms,andthesearefrequentlyreducedorsilentin
variouscancers(markedbyanasterisk).Tworeviewarticles,[65][84]andtwobroadexperimentalsurvey
articles[85][86]documentmostoftheseepigeneticDNArepairdeficiencies.
ItappearsthatepigeneticrepressionofDNArepairgenesinaccurateDNArepairpathwaysarecentralto
carcinogenesis.Howevermicrohomologymediatedendjoining(MMEJ)isanadditionalerrorprone
repairpathwayfordoublestrandbreaks.InMMEJrepairofadoublestrandbreak,anhomologyof525
complementarybasepairsonbothstrandsisidentifiedandusedasabasistoalignthestrands,butwith
mismatchedends.MMEJremovesextranucleotides(flaps)wherestrandsarejoined,thenligatesthe
strandstocreateanintactDNAdoublehelix.MMEJalwaysinvolvesatleastasmalldeletion,sothatitisa
mutagenicpathway.[30]FEN1,theflapendonucleaseinMMEJ,isepigeneticallyincreasedbypromoter
hypomethylationandisoverexpressedinthemajorityofcancersofthebreast,[87]prostate,[88]
stomach,[89][90]neuroblastomas,[91]pancreatic,[92]andlung.[93]OthergenesintheMMEJpathwayarealso
overexpressedinanumberofcancers(seeMMEJforsummary),andareshownincyan(blue)inthechart
inthissection.
DNArepairandevolution
ThebasicprocessesofDNArepairarehighlyconservedamongbothprokaryotesandeukaryotesandeven
amongbacteriophage(virusesthatinfectbacteria)however,morecomplexorganismswithmorecomplex
genomeshavecorrespondinglymorecomplexrepairmechanisms.[94]Theabilityofalargenumberof
proteinstructuralmotifstocatalyzerelevantchemicalreactionshasplayedasignificantroleinthe
elaborationofrepairmechanismsduringevolution.Foranextremelydetailedreviewofhypothesesrelating
totheevolutionofDNArepair,see.[95]
Thefossilrecordindicatesthatsinglecelllifebegantoproliferateontheplanetatsomepointduringthe
Precambrianperiod,althoughexactlywhenrecognizablymodernlifefirstemergedisunclear.Nucleicacids
becamethesoleanduniversalmeansofencodinggeneticinformation,requiringDNArepairmechanisms
thatintheirbasicformhavebeeninheritedbyallextantlifeformsfromtheircommonancestor.The
emergenceofEarth'soxygenrichatmosphere(knownasthe"oxygencatastrophe")duetophotosynthetic
organisms,aswellasthepresenceofpotentiallydamagingfreeradicalsinthecellduetooxidative
phosphorylation,necessitatedtheevolutionofDNArepairmechanismsthatactspecificallytocounterthe
typesofdamageinducedbyoxidativestress.
Rateofevolutionarychange
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Onsomeoccasions,DNAdamageisnotrepaired,orisrepairedbyanerrorpronemechanismthatresultsin
achangefromtheoriginalsequence.Whenthisoccurs,mutationsmaypropagateintothegenomesofthe
cell'sprogeny.Shouldsuchaneventoccurinagermlinecellthatwilleventuallyproduceagamete,the
mutationhasthepotentialtobepassedontotheorganism'soffspring.Therateofevolutioninaparticular
species(or,inaparticulargene)isafunctionoftherateofmutation.Asaconsequence,therateand
accuracyofDNArepairmechanismshaveaninfluenceovertheprocessofevolutionarychange.[96]Since
thenormaladaptationofpopulationsoforganismstochangingcircumstances(forinstancetheadaptationof
thebeaksofapopulationoffinchestothechangingpresenceofhardseedsorinsects)proceedsbygene
regulationandtherecombinationandselectionofgenevariationsallelesandnotbypassingon
irreparableDNAdamagestotheoffspring,[97]DNAdamageprotectionandrepairdoesnotinfluencethe
rateofadaptationbygeneregulationandbyrecombinationandselectionofalleles.Ontheotherhand,
DNAdamagerepairandprotectiondoesinfluencetherateofaccumulationofirreparable,advantageous,
codeexpanding,inheritablemutations,andslowsdowntheevolutionarymechanismforexpansionofthe
genomeoforganismswithnewfunctionalities.Thetensionbetweenevolvabilityandmutationrepairand
protectionneedsfurtherinvestigation.
DNArepairtechnology
AtechnologynamedclusteredregularlyinterspacedshortpalindromicrepeatshortenedtoCRISPRCas9
wasdiscoveredin2012.Thenewtechnologyallowsanyonewithmolecularbiologytrainingtoalterthe
genesofanyspecieswithprecision.[98]
Seealso
Acceleratedagingdisease
AgingDNA
Cellcycle
DNAdamage(naturallyoccurring)
DNAdamagetheoryofaging
DNAreplication
DirectDNAdamage
Genetherapy
Humanmitochondrialgenetics
IndirectDNAdamage
Lifeextension
Progeria
Senescence
SiDNA
ThescientificjournalDNARepairunderMutationResearch
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