BRCA1andBRCA2wereidentifiedgeneticallyasbreastcancersusceptibilitygeneswhenasinglecopyofthegeneismutatedandareinvolvedinthecellularresponsetoDNAdamage,includingblockingcellcycleprogressionandinducingDNArepairtopreservetheintegrityofthegenomeduringcelldivision.BRCA1andBRCA2inducedouble-strandedrepairofbreaksusinghomologousrecombination,inpartthroughactivationofRAD51.BRCA1actsasaubiquitinligasetargetingtheproteinFancD2thatactivatescheckpointcontrol,integratingtheATMresponsetoionizingrADIationandtheFAresponsetocross-linkingagentslikemitomycinC.MutationofoneoftheseveralcomponentsoftheFAcomplexinvolvedinmaintainingintegrityofthegenomeleadstotheconditionFanconianemia.OnememberoftheFAcomplexwasrecentlyidentifiedasBRCA2,whichleadstoFanconianemiawhenbothcopiesofthegenearemutated.AnotherrelatedfactorinvolvedintheresponseofcellstoDNAdamageisthekinaseATM(see“ATMSignalingPathway”and“cdc25andchk1RegulatoryPathwayinresponsetoDNAdamage”pathway).ATMismutatedinpatientswithAT,aconditionwithmanysimilartraitstoFanconianemia.LikeATM,ATRservesasacheckpointkinasethathaltscellcycleprogressionandinducesDNArepairwhenDNAisdamaged.LossofATRresultsinalossofcheckpointcontrolinresponsetoDNAdamage,leadingtocelldeath,anddeletionoftheATRgeneinmiceisembryoniclethal.ATRIPisaproteinthatinteractswithATRandisasubstrateforitskinaseactivity.ATRIPisrequiredforATRfunction,andremovalofATRIPalsoleadstoalossofcheckpointcontrolofthecellcycle.ATRandATMkinasetargetsincluderepairenzymeslikeRad51,andthecheckpointkinasesChk1andChk2,aswellasBRCA1andBRCA2.ThecloserelationshipofthegenesinvolvedinbreastcancerandFanconianemiahashelpedIlluminatethissignalingsystem,andmayhelpleadtoimprovedunderstandingandtreatmentoftheseconditions.

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