EpigeneticregulationofDNArepairgenesandimplicationsfortumorMarkusChristmannBerndKainaDepartmentofToxicologyUniversityofMainzObereZahlbacherStr67D55131MainzGermany CorrespondingauthorsEmailadd ID: 943192
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ContentslistsavailableatMutationResearch-ReviewsinMutationResearchjournalhomepage:www.elsevier.com/locate/mutrev EpigeneticregulationofDNArepairgenesandimplicationsfortumorMarkusChristmann,BerndKainaDepartmentofToxicology,UniversityofMainz,ObereZahlbacherStr.67,D-55131Mainz,Germany Correspondingauthors.E-mailaddresses:(M.Christmann),(B.Kaina). numerouscovalenthistonemodications,suchasacetylation,methy-lation,phosphorylationandubiquitinationatthe-terminaltailstails.Forexample,acetylationof-terminallysineresiduesofhistonesH3andH4isassociatedwithactivechromatin,whilemethylationoflysine9and27ofhistoneH3appearstobethehallmarkofcondensedchromatinatsilentlociloci–9](Fig.1A).Histonemodicationsexerttheireectsviadirectorindirectinuencingtheoverallstructureofchromatin.Histoneacetylationandphosphorylationreducethepositivechargeofhistones,thusdisruptingtheelectrostaticinteractionofpro-teinswiththeDNADNA.Opposedtothis,methylationdoesnotprovokealterationsintheoverallchargeofhistonesbutregulatesbindingofectormoleculeslikechromatinremodelersortranscriptionfactorsfactors.Histonemodicationsareregulatedbytheactionofopposingenzymepairs(Fig.1A).Acetylationoflysineisregulatedbyhistoneacetyltransferases(HATs)anddeacetylases(HDACs).Sincehistoneacetylationleadstoopeningofthechromatin,HDACsactpre-dominantlyastranscriptionalrepressors.Methylationoccurspre-dominantlyatlysineresiduesofhistones,whichcanbemono-,di-ortri-methylatedbyhistonelysinemethyltransferase(HKMT)withadenosylmethionine(SAM)asmethylgroupdonor.DemethylationismediatedbydierenthistoneLysdemethylases(KDMs),belongingtoeithertheaminooxidaseortheJmjCfamily.Generally,acetylation/deacetylationofhistonesleadstotransientalterationsingeneexpres-sion,whereasmethylation/demethylationcaneitherleadtoactivationorfacultativeandconstitutivesilencing,dependingonthehistone,theresidueandthetypeofmodication.Forstablegenesilencing,histonecationscross-talkwithmechanismsleadingtomethylationofthepromoter.BesidesregulatingchromatinstructureHDACsarealsoin-volvedinregulatingtheactivityofvariousDNArepairsystemssystems.3.DNAmethylationEnzymaticDNAmethylationoccursatthe5-Cpositionofcytosine(5-methylcytosine,5meC)inhemimethylatedCpGdi-nucleotides,socalledCpGislands.CpGislandsare0.52kBregionsthatarelocatedinthe5promoterregionsofupto50%ofallhumangenesgenes.Me-thylationofCpGislandsisfrequentlyprecededbyhistonemodiandrearrangementsofthechromosomestructure,whichnallyleadstomethylationofCpGinthetranscriptionfactorbindingsitearea(brienamedpromotermethylation)resultingintranscriptionalsilencingofthegene(Fig.1B).Centromericandpericentromericregionsaswellasotherrepetitiveelementsarestronglymethylated,andalsomanyareas Table1DNArepairgenesregulatedonepigeneticlevel.GeneCancertypeFrequencyRef.BreastCancer78%78%HeadandNeckSquamousCellCarcinoma25%[151]NonSmallCellLungCancer1919alkbh3Breastcancer27%27%brca1BreastCancer1111–115]OvarianCancer55–116,120]GastricCancer60%60%NonSmallCellLungCancer44UterineLeiomyosarcoma25%25%BladderCancer12.1%12.1%brca2BreastCancer5757DuctalCarcinomainsitusituInvasiveDuctalCancer64%64%NonSmallCellLungCancer42%42%LaryngealSquamousCellCellchk2NonSmallCellLungCancer28%28%ercc1Glioma37.5%37.5%fancCSporadicLeukemia2.5%2.5%HeadandNeckSquamousCellCarcinomaCarcinomafancFCervicalCancer30%30%NonSmallCellLungCancer14%14%OvarianCancer1313/[98]/[99]HeadandNeckSquamousCellCarcinomaCarcinomaSporadicbreastcancer11/[102]BladdercancerSinglecase(1/41)(1/41)fen1BreastCancer33.3%33.3%ku80NonSmallCellLungCancer20%20%mbd4ColorectalCancer24%24%mgmtVariousbraincancers38%38%Glioblastoma34–45%[41,45–49]IntrahepaticCholangiocarcinomas11%[213]Non-Seminomas/Seminomas69%/24%69%/24%CervixCancerCancerBladderCancerCancerHeadandNeckSquamousCellCarcinomaCarcinoma/[217]Lymphomas25%[41]ColorectalCancerCancerLungtumorstumorsPancreaticCancerCancerMelanoma11%[41]RenalCarcinomaCarcinomaLeukemia6%[41]NonSmallCellLungCancer88–221]mlh1Astrocytoma15%[76]HNPCCSingleCaseCaseAcuteMyeloidLeukemia2/552/55GastricCancerCancerHeadandNeckSquamousCellCarcinomaCarcinomaNonSmallCellLungCancer56%56%Oralsquamouscellcancer1717–81,227]OvarianCancerCancer/[82]SporadicColorectalCancer38%38%SporadicEndometrial[71][72]EpithelialOvarianCancer56.356.3T-cellleukemia/lymphoma6%6%.HeadandNeckSquamousCellCarcinomaCarcinomaGastricCancerCancerOralSquamousCellCellEsophagealSquamousCellCellPancreaticCancerCancerOvarianCancerCancerNonSmallCellLungCancer31.3% Table1GeneCancertypeFrequencyRef.Glioblastoma50%50%msh2NonSmallCellLungCancer28.6%28.6%OralSquamousCellCell–81]OvarianCancer51.7%[82]ColorectalCancer(MSH2-(MSH2-GastricCancer15.6%15.6%msh3Gastriccancer14.3%14.3%ogg1ThyroidCancer5%5%wrncolorectalcancer(37.9%);non-smallcelllungcancer(37.5%);chondrosarcomas(33.3%);gastriccancer(25%);non-Hodgkinlymphoma(23.7%);prostatecancer(20%);breastcancer(17.2%);thyroidtumors(12.5%);osteosarcomas(11.1%);acutelymphoblasticleukemia(9.5%);acutemyeloblasticleukemia(4.8%)(4.8%)OralSquamousCellCarcinoma23.8%23.8%xpcBladderCancer32.4%32.4%NonSmallCellLungCancer33.5%33.5%xrcc1Gastriccancer76,476,4M.Christmann,B.Kaina inthecodingregionofgenesshowahighdegreeofmethylation.Oncontrarytothis,CpGislandswhicharelocatedinthepromoterregionarelargelyunmethylated.Thismethylationpattern,onceestablishedisnormallymaintainedthroughoutcelldivision.However,alterationoftheepigeneticprolecanbeaccomplishedbytargeteddenovothylationanddemethylationdemethylation.CytosinemethylationisperformedbyDNA(cytosine-5)-methyl-(cytosine-5)-methyl-.WhileDNMT1functionsasamaintenancemethyl-transferasetomethylatecytosineinthenewlysynthesizedDNAstrandimmediatelyafterreplication,DNMT3AandDNMT3Bmethylatemethylate(Fig.1B).AthirdmemberoftheDNMT3family,DNMT3L,actsasaregulatorofDNMT3AandDNMT3BB.Tran-scriptionalrepressionbymethyl-CpGismediatedbyadditionalmethyl-DNAbindingproteins(MBD1,MBD2,MBD3,MeCP2andMBD4)orzincngerdomainproteins(Kaiso,ZBTB4andZBTB38)ZBTB38).Theseproteinscanfurtherrecruitchromatinremodelingfactorssuchashistonedea-cetylasesandhistoneH3lysine9methylasesmethylases.4.DNAdemethylationWhereasthemechanismofDNAmethylationiswellunderstood,themechanismunderlyingactivedemethylat
ionremainedenigmaticforlongtime.AconceivablewaytodemethylatetheDNAwouldbeanenzymaticremovalofthemethylgroupfromthe5-positionofcyto-sine.Thismechanismhoweverishighlyunlikelytooccurduetothehighstrengthofthecarboncarbonbondatthe5-positionofcytosine.Asanalternativestrategy,acut-outprocesscanbeconsidered.Thisiswhatnaturedoes.Thedetailedmechanismwasresolvedquiterecently.Itwasshownthattheremovalof5-methylcytosinerestsontheenzymaticmodicationof5-methylcytosinebytheactivation-in-duceddeaminase(AID)andtheTETmethylcytosinedioxygenasesfollowedbybaseexcisionrepairsee(Fig.2).Inmoredetail,theme-chanisminvolvesenzymaticdeaminationof5-methylcytosinetothy-minebyAID,followedbyBERorMMRthatreplacethyminewith[20].AsecondputativemechanismseemstoimplicatethefunctionofGadd45aandtheNERendonucleaseXPG[21].Inthiscase,itwasshownthatectopicexpressionofGadd45acorrelateswithapartialreductioninmethylationattheOct4promoterinXenopuslaevisoocytes.However,usinghumanGadd45ainsteadoffrogGadd45a,demethylationcouldnotbeachieved[22].Therefore,itisconceivablethatthepossibleinvolvementofGadd45aandXPGinthedemethy-lationprocessiscellspecicandpresumablyreectsanunknownroleinexcisionrepair[23,24]Mostrecentlyitwasshownthat5-methylcytosinedemethylationinvolvesthebase5-hydroxymethylcytosine(5hmC),whichwasde-scribedasthesixthbaseofthemammaliangenomegenome.5hmCisgeneratedfrom5meCaFe(II)andalpha-ketoglutarate(pendentoxidationreactionreaction.ThereactionismediatedbytheTET(teneleventranslocation)methylcytosinedioxygenases(TET1-3),whichalsocatalyzestheconversionof5hmCto5-formylcytosine(5fC)andfurtherto5-carboxylcytosine(5caC).5fCand5CaCaresubstratesfortheTDGandthereforecanberepairedbyBERBER.Analternativeinvolvesdeaminationof5hmCto5-hydroxymethyluracil(5hmU)byAID,followedbySMUG1,UNGandTDGmediatedBERBER.Inaddition,theglycosylasesNEIL1,2and3canpartiallysub-stituteTDGinthisprocessprocess(Fig.2 Fig.1.Mechanismsofepigeneticgeneregulation.A)Histonemodicationisregulatedbyopposingen-zymes.Acetylationoflysineismediatedbyhistoneacetyltransferases(HATs)anddeacetylationbyhis-tonedeacetylases(HDACs).Methylationismediatedbyhistonelysinemethyltransferase(HKMTs)anddemethylationbyhistonelysinedemethylases.DNAmethylationat5-methylcytosine(5meC)isperformedbyDNA(cytosine-5)-methyltransferases(DNMT1,DNMT3AandDNMT3B)whereasde-methylationisaccomplishedbyTETmethylcytosinedioxygenases(TET1-3),theactivation-induceddea-minase(AID),Gadd45a/XPG,andtheglycosylasesTDG,UNG,NEIL1/23.M.Christmann,B.Kaina 5.RegulationofDNArepairgenesbypromotermethylation5.1.EpigeneticregulationofMGMTRegardingepigeneticregulationofgenes,themostintensivelystu-diedDNArepairgeneisthealkyltransferaseMGMTMGMT.Asmanyas97CpGislandshavebeenidentiedinthepromoterandmethylationoftwoCpGclusterspositionedbetween249andandbetween+107and+196havebeenshowntoprovoketranscrip-tionalsilencingsilencing–36].Undernon-methylatedconditions,thetran-scriptionstartsiteisankedbyfourpreciselypositionednucleosome-likestructures(Fig.3A).MethylationoftheCpG-islandsresultsinheterochromatinization,whichisaccomplishedbythere-arrangementofthesenucleosomes,whichnowshieldthetranscriptionstartsitefromthetranscriptionmachinerymachinery(Fig.3B).Asexpected,methy-lationoftheCpG-islandswithinthepromoterstronglycorrelateswithMGMTactivity(Fig.3C).Besidesmethylationofthepromoter,methylationwithinthebodyofthegenehasbeenshowntoimpactonMGMTexpression.Inthiscase,methylationintheexon-containingregionsresultedinup-regulationofMGMTexpressionexpression,whichwasaccompaniedbyacquiredresistanceofmelanomacellstotheantic-ancerdrugfotemustinefotemustine.InactivationofMGMTbypromoterhypermethylationisacommoneventinvariousprimaryhumancancerslikeglioma,headandneckcancer,lymphoma,colorectalandlungtumors,pancreaticcarcinoma,melanoma,renalcarcinoma,leukemiaandbladdercarcinomacarcinoma.Itwasnotatallobservedinbreastcancer,ovariancanceranden-dometrialcancer(forreviewseesee–44]).Mostanalyseswerecon-ductedinglioblastoma,showingepigeneticsilencingofMGMTin45%ofthecasescases–49].MGMTpromotermethylationwasalsoobservedinupto33%ofrecurrentgliomaglioma–51].AsMGMTisthemaindeterminantofthecellssensitivitytomethylatingandchloroethylatinganticancerdrugsdrugs,itsexpres-sionlevellevel(Fig.3D)aswellasthemethylationstatusofthepromoter(Fig.3E)correlatewiththesurvivalofglioblastomapatientstreatedwiththesedrugs.Promotermethylationofisthereforeusedasaprognosticmarkerforthetherapeuticresponseofglio-blastomapatientstreatedwithalkylatingagents,i.e.themethylatingdrugtemozolomideandthechloroethylatingagentlomustine(CCNU)ornimustine(ACNU)(ACNU).Similartoglioblastomapatients,alsomelanomapatientsiname-case,notablywithbrainmetastases,undergotreatmentwithalkylatingagents.Overall,methylationwasdetectedin29.7%29.7%,31%31%and34%34%ofmetastaticmalignantmelanoma.IndisseminatedcutaneousmelanomamelanomaandmetastaticmelanomamelanomaanassociationbetweenpromotermethylationandtheresponsetoTMZtreatmentwasobserved,andgenepromotermethylationwasassociatedwithlongersurvivalofpatientssueringfrommeta-staticmelanoma,irrespectiveoftherapytherapy.MGMTpromotermethylationalsorepresentsafrequenteventinthedevelopmentofcolorectalcancer[59].Inthistypeofcancer,noasso-ciationwiththerapyresponsewasobserved.Ofnote,thesetumorsarenotsubjectoftreatmentwithalkylatingagents,whichmightexplainthislackofcorrelation.Indetail,MGMTpromoterhypermethylationwasobservedin38%of855colonandrectalcancers,andnoassociationwithpatientsurvivalwasobserved[60].Inaddition,MGMTpromoterme-thylationwasdetectedin64.2%ofbrainmetastasesfromcolorectalcancer,andthetherapeuticoutcomewasagainindependentoftheMGMTstatus[61].Arecentmeta-analysisshowedthatMGMTpromotermethylationiscentraltothedevelopmentofcolorectalcancer,butisnotassociatedwiththeprognosis[62]MGMTpromotermethylationwasfurtherobservedinbrainmetastasesderivedfromlungcancer(46.5%),breastcancer(28.8%),malignantmelanoma(24.7%)andrenalcancer(20%)[63],aswellasinseveralothercancerentities(Table1 Fig.2.Metabolismof5-methylcytosine.M.Christmann,B.Kaina InadditiontoMGMT,the-ketoglutaratedependentdioxygenasesALKBH2andALKBH3(repairenzymeshomologousofE.coliprotein)areinvolvedinthedirectreversalofalkylationdama
ge.Thus,ALKBH2andALKBH3catalyzestheremovalof1-methyladenineand3-methylcytosine,whicharebothsupposedtobecytotoxiclesionslesions.InarecentstudyitwasshownthatthehumanALKBH3promoterismethylatedin27%ofthecases,whichwasassociatedwithreducedsurvivalofbreastcancerpatientspatients.5.2.Epigeneticregulationofmismatchrepair(MMR)MMRisresponsibleforthedetectionandrepairofsinglebasemismatchesandsmallinsertion/deletionmismatchesgeneratedduringreplication.DuringrepairthemismatchisrecognizedbytheMutScomplex(MSH2andMSH6).UponinteractionwithMutL(MLH1andPMS2),thecomplextranslocatesalongtheDNAinsearchforpre-ex-istingSSBs.TheseSSBsariseattheendoftheOkazakifragmentsorresultfromRNAseHmediatedremovalofuracilinthenewlysynthe-sizedDNAstrand.StartingfromthisSSB,theexonucleaseEXO1,to-getherwiththeMutSandMutLcomplextransclocatesback,therebyremovingthenewlysynthesizedDNAcontainingthemismatch.DefectsinMMRleadtomicrosatelliteinstabilitythatiscausallyinvolvedinthedevelopmentofhereditarynon-polyposiscoloncancer(HNPCC,Lynch-Syndrome)andinseveralsporadicdevelopingcancertypestypes,MethylationofthepromoterhasrstbeenobservedinHNPCCandithasbeenshownthatmethylationinthepromoterregionofMLH1correlateswithdecreasedactivityofthegenegene.Methyla-tionofthepromoterhighlycorrelateswithmicrosatellitein-stability(MSI).Thus,promotermethylationwasfoundnearlyexclusivelyinMSI+tumorscomparedtoMSI-cancersfromthesamesame–73].IncontrasttoMGMT,thepromotermethylationstatusisnotyetbeingusedasaprognosticmarker.Itcouldbethathypermethylationisacommoneventintheformationofcoloncancer.Inthiscasetheso-calledCpGislandmethylatorphenotype(CIMP)isbeingobserved,whichismarkedbymethylationofmultiplepromoterCpGislands.Interestingly,inalargestudyanalyzing649coloncancers,patientswithtumorsharboringatleast6outof8methylatedCIMP-cpromoters(amongstthemthepromoter)showedalowercoloncancerspecicmortalitymortality.MLH1promotermethylationwasalsoobservedinadvanced Fig.3.PromotermethylationofMGMT.Withinthepromoter,thetranscriptionstartsiteisankedbyfournucleosome-likestructuresallowingtranscription.UponmethylationoftwoCpGclusterspositionedbetween249and103andbetween+107and+196re-arrangementofthesenucleosomesoccurs,shieldthetranscriptionstartsiteandpreventingM.Christmann,B.Kaina epithelialovariancancer,howeveronlyrecurrences,butnotprimarytumorsshowedpromotermethylationmethylation.Inthiscase,methylationofpromoterwasassociatedwithacquiredresistancetocisplatinandcarboplatincarboplatin.Concerningtheresponsetoanticancertherapy,asecondreportforastrocytomaisavailable.Here,promotermethylationwasassociatedwithlongerprogression-freesurvivalupontreatmentwithACNUACNU.Methylationofthepromoterwasalsoobservedinheadandnecksquamouscellcarcinoma,esophagealsquamouscellcarcinoma,oralsquamouscellcarcinoma,NSCLC,gastriccancer,pancreaticcancer,endometrialcarcinomaandleukemiaTable1IncomparisontoMLH1,MSH2appearstobelessintensivelyregulatedbypromotermethylationsinceseveralstudies,inwhichpromotermethylationwasanalysed,werenegativeastomethylationofthepromoter.Nevertheless,methylationwasobservedincolorectalcancercancer,NSCLCNSCLC,oralsquamouscellcancer(OSCC)(OSCC)–81]andovariancancercancer.Inter-wasalsofoundtobemethylatedin33%ofneurobromatosistype1patientspatients.MSH3representsanadditionalfactorinMMR.TogetherwithMSH2itformstheheterodimerMutS,whichcorrectslonginsertion/deletionloopsmicrosatellitesduringDNAsynthesis.Thepromoterwasfoundtobemethylatedandepi-geneticallyinactivatedingastriccarcinomacarcinoma.5.3.Epigeneticregulationofnucleotideexcisionrepair(NER)SimilartoMMR,adeciencyinNERgeneexpressionisassociatedwithgenomicinstabilitysyndrome,leadingtoenhancedcancerin-cidence.ThusmutationsinNERgenesresultinthewell-knownher-editaryDNArepairdefectsxerodermapigmentosumssyndrome.Interestingly,epigeneticsilencingofNERgeneswasfoundtobeassociatedwithhyper-sensitivitytoanticancerdrugs.NERconsistsoftwodistinctpathways,namelyglobalgenomicrepair(GGR)andtranscription-coupledrepair(TCR).DuringGGR,theDNAdamageisrecognizedbytheXPCHR23BandDDB1-DDB2complexesandfurtherveriedbyXPA.TFIIHcontainingthetwoDNAhelicasesXPBandXPDunwindstheDNAstrandandthedamagedDNAstrandisincisedbytheendonucleasesERCC1-XPFandXPG.UponremovalofthedamagedDNAregion,DNAsynthesisandligationoccurs.DuringTCRtheDNAlesionisdetectedblockageofRNAPII,leadingtoassemblyofCSAandCSBatthesiteofthelesion.Uponback-trackingorremovalofRNAPIICSBinteractswithXPG,initiatingDNArepairsimilartoEpigeneticsilencingofNERgeneshasbeenreportedonlyinfewreports.Thus,astudydescribedmethylationofmurinecellsandfurtherdetectedmethylationin5outof26humanovariancancercancer.Therearealsoreportsdescribingepigeneticsilencingof.Thepromotercomprisesaregionbetween5503and5280.Inthisregion,CpGhypermethylationwasobservedin3outof5gliomacelllinesandin12outof32ofgliomatumorsamplessamples.Moreover,itwasshownthatmethylationofthepromoterinverselycorrelateswiththeexpressionofmRNA,ERCC1proteinandcisplatinsensitivity.Ingliomacellpromotermethylationwasalsoassociatedwithradio-radio-.Thegenecontains47CpGsandCpAsbetween338and64.Methylationofthesesiteswasreportedininterleukin-6responsivemyelomaKAS-6/1cells.Intheseexperimentspromotermethylationcorrelatedwithgeneexpressionexpression.Onlylim-iteddataisavailableforthepresenceofthesemethylationinhumancancers.Thusinfrequentmethylation(2%)inbeendescribedinnon-smallcelllungcancercancer.Thecontains17CpGislandsbetweennucleotides175and1andhy-permethylationofthisregioncorrelateswithXPCexpressioninlungcancercelllineslines.XPChypermethylationwasfurtherdetectedin33.5%oflungcancerswhereitwaspredominantlyfoundinnon-smokers(41%)comparedtosmokers(22%)andwasalsoobservedinbladdercancertissuetissue.Concerning),hypermethylationofoneCpGsitewasfoundtobeassociatedwithgenerepressioninthelenstissuefrompatientssueringfromage-relatednuclearcataractcataract.5.4.EpigeneticregulationofinterstrandcrosslinkrepairDNAinterstrandcross-links(ICLs)covalentlyconnecttheDNAstrandsandthusleadtoblockageofDNAreplicationandtranscriptionnallycelldeath.Duetothehightoxicityofthisprocess,antic-ancerdrugsinducingICLs,likecisplatin,arewidelyused.ICLsarere-pairedbythecombinedactionofvariousDNArepairproteinsbe-longingtodierent
repairmechanismssuchasNER,homologousrecombinationandtranslesionsynthesis.ImportantcomponentsofICLrepair,thatdetectandcoordinatethesemechanisms,areFanconian-(FANC)proteins.Deciencyineitheroneofthese15proteinsresultsin,agenomicinstabilitydisorderwithhighin-cidenceofcancer.IntheFanconipathwayeightFANCproteins(FANC-A,B,C,E,F,G,L,M)formacomplexthatdetectsICLandsubsequentlymono-ubiquitinatestwootherFANCproteins(FANCD2andFANCI),leadingtotheiractivation.FANCD2interactswiththeFANCN/FANCD1(BRCA2)complexandtherebyregulateshomologousrecombination.Inaddition,FANCD2interactswithBRCA1,whichinturncaninteractwiththehelicaseFANCJ,therebyenhancinghomologousrecombina-tionandinhibitingtranslesionsynthesissynthesis,orwiththenucleaseFAN1,whichisinvolvedintheincision/excisionstep.Initiallyithasbeenshownthatthepromotercontains61potentialmethylationsiteswithinthenucleotides330to+440+440.Thisregionwashypermethylatedin4outof25ovariancancercelllinesandin4outof19ovarytumors,andhypermethylationwasshowntobeassociatedwithsensitivitytocisplatincisplatin.Inaddition,hypermethy-lationwasobservedin36outof112epithelialovariancancers,whichwasassociatedwithprognosisprognosis,aswellasincervical,cervical,,lunglungandovariancancercancer–100],andatverylowfrequencyinsporadicbreastbreastandbladdercancercancer.Experimentally,hypermethylationofhasbeenreportedinSiHacellsaftertreatmentwithcurcumin,resultinginavefoldupregulationofgenegene.Hypermethylationofthepromoterwasob-servedin1/143AMLbonemarrowsamplesand3/97acutelympho-blasticleukemia(ALL)samples,whichwascorrelatedwithincreasedsensitivitytomitomycinCC.Hypermethylationofthepromoterwasalsoreportedinheadandneckcancercancer.Further-morealsohypermethylationofthepromoterwasobservedin1/97ALLsamplessamples.PromotermethylationofwhichrepresentsthepartnerandlocalizerofBRCA2wasreportedin2/8inheritedbreasttumors,4/60sporadicbreasttumors,aswellasin4/53sporadicovariantumorstumors.Mutationsinthegene(BreastCancer1,early-onset)highlypredisposetothedevelopmentofcertaintypesofcancerssuchasbreast,ovaryandprostatecancer.Similartomutationalinactivationof,promotermethylationofisalsohighlyassociatedwithsporadicbreastcancer,assummarizedinameta-analysisof40studiesstudies.Initially,promotermethylationwasobservedinsporadiccancersamplesbySouth-westernanalysisanalysis.Amoreextensiveworkidentiedapromoterregion(nucleotides567to+26)thatcontains30CpGdinucleotides.Methylationofthisregionwasobservedinasporadicbreastcancercelllineline.Methylationoftheregionupstreamof728isnotassociatedwithexpression.Onlyme-thylationoftheregiondownstreamof728wasassociatedwithhis-tonehypoacetylation,chromatincondensationandsilencingofthegeneintumorcelllineslinesandin3outof21breastcancersamplessamples.Uptonowmethylationofthepromoterwasobservedinbreastbreast–115]andinovariancancercancer–116]whereitwasassociatedwithpoorpatientoutcomeoutcome.Furtheranalysisshowedthatpromotermethylationalsorepresentsafavorableindependentprognosticfactorinbreastcancerpatientspatients.M.Christmann,B.Kaina Besidesbreastandovariancancer,hypermethylationofthepromoterwasobservedinlungcancercancer,gastriccancercancer,NSCL[45,97],uterinecancercancer,andbladdercancercancer.Inadditiontohypermethylation,alsohypomethylationofgenescodingforinterstrandcrosslinkrepairwasreported.Thus3/58primarylaryngealcasesshowedhypomethylationofandalltumorsshowedatthesametimehypomethylationinthepromoterofthethe.5.5.Epigeneticregulationofbaseexcisionrepair(BER)efectsinNER,ICLandDDRareassociatedwithinheritedchro-mosomalinstabilitysyndromes.ThisseemsnottobethecaseforBER.However,alterationsinBERactivityarelinkedtoavarietyofneuro-degenerativediseaseslikeAlzheimerdisease,multiplesclerosis(MS)andParkinsonParkinson.Theyalsoseembelinkedtoagingaging.TheroleofBERincancerformationislesssubstantiatedbyexperimentalevi-dence.Whereasenhancedlevelsof8-OxoGhavebeenfoundinmultipletumors,nomutationsofBERgeneshavebeendetected.Thiscouldbeduetothefactthatatleastinmice,knockoutofkeyBERproteinsisembryoniclethal.However,inseveralcasesanassociationbetweenpolymorphismsinBERgenesandcancerincidencehasbeenfound.IthasalsobeenreportedthatimbalancesinBERgeneexpressionareassociatedwithcancerformationorprogressionprogression.ConcerningepigeneticregulationofBERgenes,onlylimiteddataareavailable.TheypertainnotablytheregulationoftheDNAglyco-sylasesMBD4,MPG,OGG1,NEIL1andTDG.TheglycosylaseMBD4removesthyminefromT:Gmismatches,whicharetheproductofdeaminationof5-methylcytosineatCpGsitessites.Withinthepromoter,aCpGislandwasidentiedthatisfrequentlymethylatedinovarianandcolorectalcancercelllinesdisplayingareducedMBD4MBD4.Incolorectalcancermethylationofthemoterwasobservedin24%ofthecases,howevernocorrelationbe-tweenmethylationandtumourstagewasobservedobserved.Theproximal(N-methylpurine-DNAglycosylase)promotercontains17CpGis-landsclosetothetranscriptionalstartsiteandtheirmethylationcor-relateswithreducedMPGexpression.Promotermethylationofwasobservedinglioblastomacells,andglioblastomabiopsiesexpres-singMPGatlowlevelshowedincreasedmethylationofthethe.Thepromoterwasfoundtobemethylatedin5%ofthyroidcancerandinsomethyroidcancercelllineslines,thepromoter,wasfoundtobemethylatedinseveralmultiplemyelomacelllinesthatshoweddecreasedTDGexpressioncomparedtonormalplasmacellscells.NEIL1,besidesbeinginvolvedinBER,alsomediatesDNAdemethylation,issilencedbypromotermethylationinheadandnecksquamouscellcarcinomacarcinoma.BesidesglycosylasesalsoothergenescodingforBERgenescanbeepigeneticallysilenced.Thehumanpromotercontains2CpGislandsbetweenthenucleotidesto+278bpbp.Acomparisonbetweenbreastcancerandcorre-spondingnormaltissuerevealedincreasedmethylationofthesecondCpGislandinthenormaltissue,suggestingthatthenothypermethylated,butratherhypomethylatedintumorstumors.Moreover,areducedexpressionofAPEX1observedinpatient-derivedHuntingtondiseasecellswasassociatedwithpromoterhypermethyla-hypermethyla-.ThepromoterwashypermethylatedingastriccancercancerthePARP-1promoterwasfoundtobehypermethylatedincellsexposedtothegenotoxinbenzenebenzene.5.6.EpigeneticregulationofDNArepairgenesinvolvedinDNAdouble-strandbreakrepairDNAdoublestrandbreaksarerepairedbynon-homologousend-joining(NHEJ)
orhomologousrecombination(HR).IntheprocessofNHEJ,theproteinKu80(XRCC5)togetherwithKu70(XRCC6)andthecatalyticsubunitoftheDNA-dependentproteinkinase(DNA-PKcs)formacomplexthatdetectsDSB.InthiscomplexDNA-PKcsisactivatedandmediatesrepairviaregulationofadditionalfactorslikeArtemis,XLF,XRCC4.Analysisofthehumanpromoterrevealedthepre-senceoftwoSp1sitesat+43and+133andthepresenceofa21bppalindromicsequencethatislocated5tothedistalSp1element.Theseelements,whicharerequiredforKu80expression,canbesilencedbyby.Methylationofthepromoterwasobservedinlungcancercancer.ThishasalsobeenobservedandsupposedtobethemolecularcauseforsilencingofKu80inmatureneurocytesneurocytes.DuringHR,thedamagedchromosomeentersintophysicalcontactwithanundamagedDNAmoleculewithwhichitsharessequencehomologyandwhichisusedastemplateforrepair.HRisinitiatedbynucleolyticresectionoftheDSBbytheMRE11/Rad50/NBS1complex.Theresultingsingle-strandedDNAisthereaftercoveredbyRPAprotein,whichprotectsagainstexonucleolyticdigestion.ThereafterRAD52and/orBRCA2mediateloadingofRAD51ontoRPAboundssDNAandstimulateRAD51-mediatedstrandinvasion.TheassemblyoftheRAD51lamentisfurtherfacilitatedbyvedierentparaloguesofRad51(Rad51B,CandD;andXRCC2andXRCC3).Similartomutationsinthegenearehighlycorrelatedwiththedevelop-mentofcancerssuchasbreast,ovaryandprostatecancer.Ininitialexperiments,methylationofthethecouldneitherbeobservedinovariancancercelllinesnorinprimarysporadicbreastbreastandsporadicepithelialovariantumorstumors.Recently,however,hypermethylationofthepromoterwasdetectedinbreastcarcinomacarcinoma,ductalcarcinomacarcinoma,NSCLCNSCLCandinlaryngealsquamouscellcarcinomacarcinoma.ThediscrepancyinthendingsmightbeexplainedbydierentCpGsitesanalyzed.Thusitwasshownthatonlythepromoterregionbetweenthenucleotides59and+96,butnottheregionfrom+96to+103,showedmethylationinsporadicbreastcancercancer.BesideshypermethylationofRAD51Cwasobservedin0.5%ofpatientswithfamilialovariancancerandearly-onsetsporadicbreastcancercancer.WernersyndromeATP-dependenthelicase(WRN)representsamemberoftheRecQHelicasefamily,whichunwindandseparatedouble-strandedDNA.Itfurthercontainsa3to5exonucleaseactivitythatisusedfordegradationofprocessed3endsandinitiationofDNAdegradationfromagapindsDNA.WRNplaysanimportantroleinboththerepairofdoublestrandedbreaksandBER.Methylationofthepromoterwasextensivelyanalyzedin630primarytumorscorre-spondingto11dierenttissuetypesandobservedathighestlevelincolorectalcancer(37.9%),NSCLS(37.5%),andchondrosarcoma(33.3%)followedbygastriccancer(25%),non-Hodgkinlymphoma(23.7%),prostatecancer(20%,),breastcancer(17.2%),thyroidtumors(12.5%),osteosarcoma(11.1%),acutelymphoblasticleukemia(9.5%)andacutemyeloblasticleukemia(4.8%)(4.8%).Forcolorectalcancerithasbeenshownthatpromotermethylationconferssensitivitytotheanticancerdrugirinotecanirinotecan.Additionally,promoterhasalsobeenshowntobemethylatedinOSCCOSCC.5.7.EpigeneticregulationofDNArepairgenesassociatedwiththeDNAdamageresponseFollowingDNAdamage,theIP3-likekinasesATMandATRbecomeactivatedandphosphorylatethedownstreamkinasesCHK2andCHK1andamultitudeofothersubstratesincludingp53andseveralDNArepairproteins(forreviewseesee.MutationsinATMandATRareresponsibleforthechromosomalinstabilitysyndromes,ataxiatel-Seckelsyndrome,respectively,whicharecharacterizedbyhighcancerincidence,neurodegenerationandmalformations.HypermethylationofthepromoterwasrstobservedinradiosensitivecolorectalcellsbymethylationspecicsouthwesternanalysisusingtwoHpaII/MspIsiteslocatedwithinthepromoterpromoter.M.Christmann,B.Kaina Similartocolorectaltumorcelllines,ingliomalinesmethylationofthepromoterwasassociatedwithincreasedradiosensitivityradiosensitivity.Furthermorehypermethylationofthepromoterwasreportedinin,lunglung,recurringadenomasadenomasandbreastcancercancer.Thelatter,however,couldnotbeconrmedbyasecondstudystudy.HypermethylationofthepromoterdependsonaCpGrichregionbetweennucleotides615andand.Inthisinitialre-port,hypermethylationofwasobservedinalllungtumorsam-plesanalyzed(n=10)10).Hypermethylationofinlungcancerwasveriedinasecondreport,showingpromotermethylationin28.1%ofNSCLCs(n=139)139).Inthisstudy,themethylationfrequencywashigherinsquamouscellcarcinomathaninadenocarci-noma(40.0%vs.19.0),andwasalsohigherinever-smokerscomparedtonever-smokers(31.7%vs.17.1%).Inhumangliomaa10-foldde-creasedexpressionofgenewasobserved,whichwaspartiallyduetopromotermethylation.InthiscasehypermethylationwasshowntoinhibittheSp1bindingtothepromoter,whichresultsinattenuationofSp1mediatedmediated.6.EpigeneticsincellandcircardiancycledependentregulationofDNArepairDNArepaircanbealsoregulatedduringthecellcycleandthecir-cadianclock.ConcerningthecellcycledependentregulationofDNArepairfactors,ithasbeenshownthat58DNArepairgenesweretran-scriptionallyregulatedand30DNArepairproteinsweretranslationallyregulatedduringcellcycleprogressionprogression.However,thereisnodataindicatingon5-methylcytosinedependentepigeneticmechanismsin-Thecircadianclock,whichcontrolsthedailyrhythmicityofmanybiochemicalprocesseshasbeeninvestigatedastoregulatingDNAre-re-.However,onlynucleotideexcisionrepairseemstobecontrolledbythecircardianclockclock.Inthiscase,thecircardiantranscriptionfactorsCLOCKandBMAL1bindtothepromotersandactivateitstranscription.Besides,aweakcircadianoscillation(1.2fold)wasreportedforMGMTMGMT,theDNAglycosylaseMPGMPGandOGG1OGG1.ThisislikelyaresponseontranscriptionfactorlevelasnoevidenceisavailablethatCpGmethylationisinvolved.Acir-cardianclockdependencywasalsoreportedfortherepairofIR-inducedDNAdamageinmousesplenocytes.InthiscasecircardianoscillationofBRCA1/2,NEIL1,RAD51,RAD18,XRCC2,PMS2,,wasob-ob-,whichwashowevernotlinkedtoCpGmethylationineitheroneofthegenes.IthasalsobeenshownthatthecircadianclockcanregulatetheDNAsensitivitytoUVdamageandtheeNERbycontrollingchromatincondensationthroughhistoneacetyla-acetyla-.AlthoughthecircadianclockregulatorsPER1andPER2arecontrolledbyCpGpromotermethylationmethylation,theimpactonDNArepairstillneedstobeelucidated.7.ImpactofgenotoxicexposuresonCpGpromotermethylationWhereasthemolecularmechanismunderlyingtheCpGmethylationofpromotersiswellknown,itisstillunclearwhethertheseprocessescanberegulatedbygenotoxicstre
ss,therebycontributingtogenotoxin-inducedcarcinogenesis.Theoretically,epigeneticre-programmingmightoccurincancercellsduringtherapywithgenotoxicdrugs,whichcouldleadtomoreaggressivelygrowingtumors.Experimentalevi-denceforthisisprovidedbyseveralstudiesperformedinvitroInchemical-inducedratlungcarcinogenesis,CpGpromoterhy-permethylationof,andincreasesgraduallygradually,suggestingthatgenotoxicstressmightcontributetoepigeneticsilencingoftheserepairgenes.Furthermore,duringcadmium-inducedmalignanttransformation,anincreaseinglobalDNAmethylationwasobserved,whichwasassociatedwithoverexpressionofDNMT1andDNMT3aandpromoter-methylatedsilencingofof.Inhepatocellularcarcinoma,promoterme-thylationwasdetectedin32of83cases.ItwasassociatedwithhighlevelsofaatoxinB1DNAadductsadducts;therelevanceofthisisunclear.Alsoduringtamoxifen-inducedratlivercarcinogenesisaprogressivelossofCpGmethylationintheregulatorysequencesoflonginterspersednucleotideelements(LINE-1)wasobserved.Con-,andDNApolymerase)showedin-creasedpromotermethylation.ThesechangesinpromoterstatuswereassociatedwithdecreasedproteinexpressionofDNMT1,DNMT3a,DNMT3a,.Invitro,chronicexposuretoarsenicandestrogengaverisetopromotermethylationmethylationinhumanprostateepithelialcells,whilehypoxialettohypermethylationofthepromoterof1inMCF7MCF7.Moreover,UVB-exposureofhumanlensepitheliumB3cellsprovokedhypermethylationofthepromoterandconcomitantin-creaseinhistoneH3K9deacetylationdeacetylation.ItwasalsoreportedthatlowandhighLETirradiationsinducesepigeneticalterationsalterations.Thus,radiationleadstoglobalDNAdemethylationinhumantumorcelllinesandtheactivationofthepromotersofof.Forchemicalcarcinogens,thehematotoxinbenzenewasshowntoincreasethelevelofpromotermethylationanddecreaseexpressioninthelymphoblastoidcelllineF32F32,andfollowingB[a]PexposuremultiplepromoterhypermethylationeventsandalteredhistonemodicationswereobservedinMCF7cellscells.Theimpactofgenotoxicstressonepigeneticalterationswasalsoshowninepidemiologicalandinterventionstudies.Enhancedpro-motermethylationofwasobservedinperipheralbloodlym-phocytesofvinylchlorideexposedworkersworkersandhypomethy-lationoftheERCC2promoterwasobservedinarsenic-exposeded.Furthermore,workersexposedtodieselengineexhaustexhibitedareducedpromotermethylationlevelinperipherallymphocytes(althoughtheMGMTpromoterinlympho-cytesisactiveandconsideredtobeunmethylated)[184].Intwinswithdiscordantsmokinghabits,smoking-relatedDNAmethylationchangesin22CpGsiteswasreported[185],howevernoalterationsinthepromotermethylationofandBRCA1wasobservedved.BesidescarcinogensalsovitaminandantioxidantrichdietenhancedtheCpGmethylationofMLH1andinbloodsamplesofhumanvolunteerss.Further,supplementationofpregnantpigswithadietenrichedinantioxidantsandothernutrientsledtoreducedoxidativeDNAdamageandAPE1promotermethylationinthehippocampusofthenewborns[188].Collectively,theavailabledatasuggestthatlong-termgenotoxicexposureshaveanimpactonthemethylationstatusofDNArepairgenes.8.RegulationofDNMT1byp53followinggenotoxicstressHowcanCpGmethylationberegulatedbygenotoxicstress?ApossiblemechanismwewouldliketoproposeonthebasisofavailabledatarestsontheregulationofDNMT1byp53(Fig.4).DNMT1un-dergoesmultipleproteininteractionsandpost-translationalmoditions,leadingtoactivation,stabilizationandrecruitmenttospecisitesinthechromatinchromatin.Amongitsregulatorsareproteinsacti-vatedbyDNAdamagesuchasp53,GADD45aandPARP-1.AmainplayerintheDNAdamageresponse,p53,hastheabilitytobindtothepromoterofandtherebyacting,contrarytoitswell-knowntranscriptionalactivatingfunction,asatranscriptionalrepressorrepressor.ThisnegativeregulationiscausedbysequestrationoftheDNAboundtranscriptionfactorSp1Sp1(asoutlinedinFig.4A).ThisresultsinareducedlevelofDNMT1expressionandimpairedCpGmethylationofthegenome.Ifthisisakeymechanism,p53upregulationfollowinggenotoxicstressisanticipatedtoberelatedtoactivationofsilencedWhetherthisisthecaseneedstobeshown.Althoughtheimpactofgenotoxicstressonp53regulatingDNMT1hasbeenaddressedininvitrostudies,thedataareconicting.Thus,IRandetoposideM.Christmann,B.Kaina preventedp53frombindingtothepromoterofDNMT1leadingtoanincreaseinDNMT1DNMT1.AnotherreportshowsthatMMS,butnotMNU,depletesDNMT1protein,whichseemstobemediatedthroughp53independentdegradationofDNMT1DNMT1.Thesituationbecomesmorecomplicatedasp53andDNMT1candirectlyinteract,whichsti-mulatesDNMT1activityandincreasestheDNMT1-mediatedDNAmethylationlevellevel(Fig.4Therearenumerousstudiesdemonstratinganassociationbetweenp53statusandCpGpromotermethylation.Thus,deletionofp53inthecoloncancercelllineHCT116,andknockdownofp53inTK6cells,resultedinincreasedDNMT1expressionexpression.Mutationsinp53wereassociatedwithDNMT1overexpressioninlungtumorstumors.OverexpressionofDNMT1correlatedwiththemethylationstatusofpromotersofMLH1,MGMT,BRCA1inpancreaticcancercancer.Ad-ditionally,themethylationfrequencyofthepromoterwashigherinp53mutatedlungcancers(62%)thaninlungcancerhar-boringthep53wild-type(wt)allele(38%)(38%).Similartolungcancer,anassociationbetweenMGMTpromoterhypermethylationandp53mutationwasfoundinbraincancers(glioblastomamultiforme)multiforme).Furthersupportfortheroleofp53inthemethylationstatusofMGMTpromoterwasreportedinastudywherep53knockdownin-creasedtheexpressionofDNMT1andhistonedeacetylase1(HDAC1),whichresultedinchromatinde-condensationDNMT1mediatedme-thylationofthepromoter,whileover-expressionofp53reducedthemethylationlevelofthethe.AkeyplayerinthegenotoxicresponseisPARP-1,whichbecomesenzymaticallyactivatedfollowingbindingtoDNArepairintermediates,includingsingle-strandedDNADNA.InhibitionofPARP-1resultedinaberrantmethylationofaCpGislandlocatedinthepromoteroftheHtf9genegene.ThiscouldresultfromPARP-1interactionwithDNMT1,blockingitscatalyticactivity(Fig.4B)andtherebypreventingCpGislandsfrombecominghypermethylatedhypermethylated.AfactorinvolvedinactivationofPARP-1andinhibitionofDNMT1isthechromatinin-sulator,ortranscriptionalrepressor,CTCFCTCF.DNMT1andPARP-1caninteractwithCTCF,preventingmethylationofCTCFtargetstargets.Contrarytothestimulatingeectofp53onDNMT1,theinteractionofDNMT1withGADD45ainhibitsitsactivityactivity(Fig.4B).Theprecisemechanismisunknown.Itisimportanttonotethatp53andG
ADD45aareupregulatedpresumablybyanytypeofgenotoxicstress,p53onproteinproteinandGADD45aongenelevellevel.IfbothhaveanimpactontheregulationofDNMT1,onemightexpectthatgenotoxicstresshasadramaticimpactontheDNAmethylationlevel.This,however,seemsnottobethecase.Thereisnoevidencethatgenotoxicstressimmediatelyalterstheamountof5-methylcytosineintheDNA.Italsodoesnotcauseachangeinthepromotermethylationlevelofspecicgenes.Forex-ample,MGMTsilencinginglioblastomacellscannotsimplyberevertedbytreatmentwithalkylatingagentsorIR,althoughunderthesecon-ditionsoftreatmentp53andGADD45awereinduced(unpublisheddata).Itisconceivable,however,thatchronicgenotoxicexposurehasamoreprofoundeectonpromotermethylation/demethylationthangenotoxintreatment.9.RegulationofDNArepairgenesbyHDACsandSIRTsAlthoughthisreviewfocusesonregulationofDNArepairbyCpGpromotermethylation,webrieycommentontheroleofhistonecations,whichcanhaveaninuenceontheexpressionofDNArepairgenes.AlthoughtheimpactofhistonemodicationsontheexpressionofDNArepairgenesisdiculttoassess,severalstudiesindicatethatalterationsinhistonecompositionhaveanimpactonrepairgeneexpression.Thus,sodiumbutyrate,whichinhibitsclassIandclassIIAHDACsinduceshyperacetylationofhistoneH4.ThisledtodownregulationofKU70,KU80andDNA-PKcsmRNAandproteininmelanomacells,causingsensitizationtoionizingradiation[205]DownregulationoftheseDNArepairproteinswasalsoobservedfol-lowingtreatmentwiththepan-HDACinhibitortrichostatinAinnon-smallcelllungcancercells[206].Inlinewiththis,thepan-HDACinhibitorSAHAcauseddownregulationofKu80inosteosarcomaandrhabdomyosarcomacellsandsensitizedthemtoionizingradiation[207].BesidesNHEJ,alsoHRcanberegulatedbyHDACs.Thus,in-hibitionofclassIHDACsinprostatecancercellsbyvalproicacidre-ducedtheexpressionofgenesinvolvedinHRsuchasRAD51,CHK1andBRCA1.Thiswascausedbyreducedrecruitmentofthetran-scriptionfactorE2F1tothepromoterofthecorrespondinggenes,whichledtoincreasedsensitizationtoradiationandchemicalgeno-[208].BRCA1wasalsoreportedtobedownregulatedbytri-chostatinA,leadingtoenhancedradiationsensitivityofcarcinomacells[209].DecreasedexpressionofRAD51andreducedHRactivitywasalsoobservedinmalignantmelanomacellsuponpharmacologicinhibitionofclassIHDACs(byMS-275;entinostat)andknockdownofHDAC2,whichresultedininecientrepairofDSBsandsensitizationtotemozolomide[210] Fig.4.Mechanismofp53-mediatedregulationofDNMT1.A)transcriptionalregulation,B)post-translationalregulation.M.Christmann,B.Kaina 10.ConclusionsDNArepairisessentialformaintaininggenomicstabilityandpro-tectingcellsagainstendogenousandexogenousDNAdamaginginsults.Itisalsorequiredforspeciccellularprocessessuchasimmunoglobulincation.DNArepairistightlytissue-specicregulatedandfre-quentlyderegulatedincancercells.RegulationofDNArepairoccursonpost-translational,post-transcriptional(viamiRNA)andtranscriptionallevel.Thelatterinvolvestranscriptionfactorslikep53,AP-1andNF-kB,whichregulateDNArepairduringtheimmediatestressresponse.Itisalsoregulatedepigeneticallyby5-methylcytosineinCpGislandsinthepromoterandbyhistonemodications.Therepairgenemostex-tensivelyregulatedbyCpGpromotermethylationisMGMT.Thiscor-respondsinthehypermethylatedstatuswithgenesilencing,lackorlowlevelofexpressionofMGMTprotein,drugsensitivityandabetteroutcomefollowingalkylationbasedtherapy.WhileMGMTispromotermethylatedinupto45%ofbraincancersandothertumorgroups,otherrepairgenesarelessfrequentlysilencedbypromotermethylation.Thereasonforthisisunclear.CpGmethylationrequiresdenovotransferases(DNMT)whiledemethylationisdependentonTETandbaseexcisionrepairenzymes.Thus,ontheonehandDNArepairisrequiredforregulatingtheepigeneticswitchand,ontheother,itisitselfsubjectofepigeneticregulation.WhileacuteDNAdamagedoesnotimmediatelychangetheCpGmethylationlevel,thereareexamplesthatchronicexposurehasanimpactonepigeneticreprogramming.AlthoughitiswellestablishedthatepigeneticsilencingofrepairgeneslikeMGMThasaprofoundeectoncancertherapywithmonofunc-tionalalkylatingagents,itsimpactontherapywithotheranticancerdrugsremainstobeelucidated.Italsoremainstobeseentowhatextentepigeneticsilencingofrepairgenesdeterminestissuespecicdiencesinrepaircapacityandcontributestoageingandgenotoxintrig-gereddiseases.WorkwassupportedbyGermanResearchCouncil(DFGKA724)andGermanCancerAid.WearegratefultoDr.W.P.Roosforcriticalreadingthemanuscript.manuscript.J.H.Hoeijmakers,DNAdamage,aging,andcancer,N.Engl.J.Med.361(2009)(2009)M.Christmann,M.T.Tomicic,W.P.Roos,B.Kaina,MechanismsofhumanDNArepair:anupdate,Toxicology193(2003)33M.Christmann,B.Kaina,TranscriptionalregulationofhumanDNArepairgenesfollowinggenotoxicstress:triggermechanisms,inducibleresponsesandgenotoxicadaptation,NucleicAcidsRes.41(2013)84038403A.Bird,Perceptionsofepigenetics,Nature447(2007)396396S.Khorasanizadeh,Thenucleosome:fromgenomicorganizationtogenomicreg-ulation,Cell116(2004)259259T.Zhang,S.Cooper,N.Brockdor,Theinterplayofhistonemoditersthatread,EMBORep.16(2015)14671467B.D.Strahl,C.D.Allis,Thelanguageofcovalenthistonemodications,Nature403(2000)4141B.M.Turner,Readingsignalsonthenucleosomewithanewnomenclatureforedhistones,Nat.Struct.Mol.Biol.12(2005)110110T.Kouzarides,Chromatinmodicationsandtheirfunction,Cell128(2007)(2007)A.J.Bannister,T.Kouzarides,RegulationofchromatinbyhistonemodiCellRes.21(2011)381381M.Yun,J.Wu,J.L.Workman,B.Li,Readersofhistonemodications,CellRes.21(2011)564564W.P.Roos,A.Krumm,ThemultifacetedinuenceofhistonedeacetylasesonDNAdamagesignallingandDNArepair,NucleicAcidsRes.44(2016)1001710017R.L.Momparler,V.Bovenzi,DNAmethylationandcancer,J.Cell.Physiol.183(2000)145145Y.Bergman,H.Cedar,DNAmethylationdynamicsinhealthanddisease,Nat.Struct.Mol.Biol.20(2013)274274M.G.Goll,T.H.Bestor,Eukaryoticcytosinemethyltransferases,Annu.Rev.Biochem.74(2005)481481T.Chen,E.Li,StructureandfunctionofeukaryoticDNAmethyltransferases,Curr.Top.Dev.Biol.60(2004)5555D.Bourc'his,G.L.Xu,C.S.Lin,B.Bollman,T.H.Bestor,Dnmt3Landtheestab-lishmentofmaternalgenomicimprints,Science294(2001)25362536G.J.Filion,S.Zhenilo,S.Salozhin,D.Yamada,E.Prokhortchouk,P.A.Defossez,AfamilyofhumanzincngerproteinsthatbindmethylatedDNAandrepresstranscription,Mol.Cell.Biol.26(2006)169169R.J.Klose,A.P.Bird,GenomicDNAmethylation:themarkand
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