Rad3ATR Decorates Critical Chromosomal Domains with γH2A to Protect Genome Integrity during S-Phase in Fission Yeast 英文参考文献.docVIP

Rad3ATR Decorates Critical Chromosomal Domains with γH2A to Protect Genome Integrity during S-Phase in Fission Yeast 英文参考文献.doc

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Rad3ATR Decorates Critical Chromosomal Domains with γH2A to Protect Genome Integrity during S-Phase in Fission Yeast 英文参考文献

Rad3ATR DecoratesCriticalChromosomalDomainswith cH2AtoProtectGenomeIntegrityduringS-Phasein FissionYeast SophieRozenzhak1,EvaMej?′a-Ram?′rez1,JessicaS.Williams2,LanaSchaffer3,JenniferA.Hammond3, StevenR.Head3,PaulRussell1,4* 1DepartmentofMolecularBiology,TheScrippsResearchInstitute,LaJolla,California,UnitedStatesofAmerica,2LaboratoryofStructuralBiology,NationalInstituteof Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America, 3DNA Array Core Facility, The Scripps Research Institute, La Jolla, California,UnitedStatesofAmerica,4DepartmentofCellBiology,TheScrippsResearchInstitute,LaJolla,California,UnitedStatesofAmerica Abstract Schizosaccharomyces pombe Rad3 checkpoint kinase and its human ortholog ATR are essential for maintaining genome integrityincellstreatedwithgenotoxinsthatdamageDNAorarrestreplicationforks.Rad3andATRalsofunctionduring unperturbedgrowth,althoughtheeventstriggeringtheiractivationandtheircriticalfunctionsarelargelyunknown.Here,we use ChIP-on-chip analysis to map genomic loci decorated by phosphorylated histone H2A (cH2A), a Rad3 substrate that establishesachromatin-basedrecruitmentplatformforCrb2andBrc1DNArepair/checkpointproteins.Unexpectedly,cH2A marksadiversearrayofgenomicfeaturesduringS-phase,includingnaturalreplicationforkbarriersandaforkbreakagesite, retrotransposons,heterochromatininthecentromeresandtelomeres,andribosomalRNA(rDNA)repeats.cH2Aformationat thecentromeresandtelomeresisassociatedwithheterochromatinestablishmentbyClr4histonemethyltransferase.Weshow thatcH2AdomainsrecruitBrc1,afactorinvolvedinrepairofdamagedreplicationforks.Brc1C-terminalBRCTdomainbinding tocH2AiscrucialintheabsenceofRqh1Sgs1,aRecQDNAhelicaserequiredforrDNAmaintenancewhosehumanhomologs are mutated in patients with Werner, Bloom, and Rothmund–Thomson syndromes that are characterized by cancer- predispositionoracceleratedaging.WeconcludethatRad3phosphorylateshistoneH2AtomobilizeBrc1tocriticalgenomic domainsduringS-phase,and

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