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1、MolecularmechanismsofDNAdouble・strandbreakrepairRolandKanaar,JanH.J.HoeijmakersandDikC.vanGenDNAdouble・strandbreaks(DSBs)aremajorthreatstothegenomicintegrityofcells.Ifnottakencareofproperly,theycancausechromosomefragmentation,lossandtranslocation,possi
2、blyresultingincarcinogenesis.UponDSBformation,cell-cyclecheckpointsaretriggeredandmultipleDSBrepairpathwayscanbeactivated.RecentresearchontheNijmegenbreakagesyndrome,whichpredisposespatientstocancer,suggestsadirectlinkbetweenactivationofcell-cyclecheck
3、pointsandDSBrepair.Furthermore,thebiochemicalactivitiesofproteinsinvolvedinthetwomajorDSBrepairpathways,homologousrecombinationandDNAend-joining,arenowbeginningtoemerge.ThisreviewdiscussesthesenewfindingsandtheirimplicationsforthemechanismsofDSBrepair.
4、TheintegrityofDNAinsidecellsisconstantlybeingchallengedbyendogenousandexogenousDNA-damagingagents.BecausealargevarietyoflesionscanoccurinDNA,itisnotsurprisingthatmultiplepathwayshaveevolvedthateachrepairasubsetoftheselesions1•ThesignificaneeofDNArepair
5、isillustratedbythephenotypesofxerodermapigmentosum,Cockayne'ssyndrome,trichothiodystrophyandhereditarynonpolyposiscolorectalcancerpa2,3.ThesedisordersarecausedbymutationsinDNArepairgenesthatpredisposethepatientstocancer,neurologicalabnormalitiesorboth.
6、Inaddi-tiontoefficientDNArepair,correctactivationofcell-cyclecheckpointsuponinductionofDNAdamageisofcrucialimportaneeforthemaintenanceofgenomicintegrity.CheckpointsallowactivelydividingcellstopauseandrepairDNAdamagebeforesegregationofthereplicatedgenom
7、eintodaughtercells.TheirimportaneeisunderscoredbyinheriteddisordersassociatedwithdefectsinactivatingcellcyclecheckpointssuchasataxiatelangiectasiaandNijmegenbreakagesyndrome4,5.ThesedisorderscausehypersensitivitytoDNA-damagingagentsandspontaneouschromo
8、somalinstability.Inthisreview,wefocusonmechanismsofDNAdouble-strandbreak(DSB)repairDSBsaregeneratedbyendogenouslyproducedradicalsandexogenousagentssuchasionizingradiation(IR),whichisoftenusedinanti-cancertherapy・RepairofDSBsisofcardinal
