ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells 英文参考文献.docVIP

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ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells 英文参考文献.doc

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ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells 英文参考文献

ATR-p53RestrictsHomologousRecombinationin ResponsetoReplicativeStressbutDoesNotLimitDNA InterstrandCrosslinkRepairinLungCancerCells BiancaM.Sirbu1,SarahJ.Lachmayer1,2.,VerenaWu¨lfing1,2.,LaraM.Marten1,2.,KatieE.Clarkson1, LindaW.Lee1,LilianaGheorghiu1,LeeZou3,5,SimonN.Powell4,JochenDahm-Daphi2,5 ,Henning Willers1,6 * 1Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, United States of America, 2Department of Radiation Oncology, University of Hamburg, Hamburg, Germany, 3Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown,Massachusetts,UnitedStatesofAmerica,4DepartmentofRadiationOncology,MemorialSloanKetteringCancerCenter,NewYork,NewYork,UnitedStates ofAmerica,5InstituteofRadiobiologyandMolecularRadiationOncology,UniversityofMarburg,Marburg,Germany,6HarvardMedicalSchool,Boston,Massachusetts, UnitedStatesofAmerica Abstract Homologousrecombination(HR)isrequiredfortherestartofcollapsedDNAreplicationforksanderror-freerepairofDNA double-strandbreaks(DSB).However,unscheduledorhyperactiveHRmayleadtogenomicinstabilityandpromotecancer development.ThecellularfactorsthatrestrictHRprocessesinmammaliancellsareonlybeginningtobeelucidated.The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardianofthegenome,wouldimpairanerror-freerepairprocess.Here,weshowforthefirsttimethatp53downregulates fociformationoftheRAD51recombinaseinresponsetoreplicativestressinH1299lungcancercellsinamannerthatis independentofitsroleasatranscriptionfactor.WefindthatthisdownregulationofHRisnotonlycompletelydependent onthebindingsiteofp53withreplicationproteinAbutalsotheATR/ATMserine15phosphorylationsite.Geneticanalysis suggests that ATR but notATMkinase modulates p53’sfunction in HR.The suppression of HR byp53 canbe bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53’s role as a gu