Evidence for Abasic Site Sugar Phosphate-Mediated Cytotoxicity in Alkylating Agent Treated Saccharomyces cerevisiae 英文参考文献.docVIP

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Evidence for Abasic Site Sugar Phosphate-Mediated Cytotoxicity in Alkylating Agent Treated Saccharomyces cerevisiae 英文参考文献.doc

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Evidence for Abasic Site Sugar Phosphate-Mediated Cytotoxicity in Alkylating Agent Treated Saccharomyces cerevisiae 英文参考文献

EvidenceforAbasicSiteSugarPhosphate-Mediated CytotoxicityinAlkylatingAgentTreatedSaccharomyces cerevisiae MichelleHeacock.,VladimirPoltoratsky.¤,RajendraPrasad,SamuelH.Wilson* LaboratoryofStructuralBiology,NationalInstituteofEnvironmentalHealthSciences,NationalInstitutesofHealth,ResearchTrianglePark,NorthCarolina,UnitedStatesof America Abstract To better understand alkylating agent-induced cytotoxicity and the base lesion DNA repair process in Saccharomyces cerevisiae,wereplacedtheRAD27FEN1openreadingframe(ORF)withtheORFofthebifunctionalhumanrepairenzymeDNA polymerase(Pol)b.Theaimwastoprobetheeffectofremovaloftheincisedabasicsite59-sugarphosphategroup(i.e.,59- deoxyribose phosphate or 59-dRP) in protection against methyl methanesulfonate (MMS)-induced cytotoxicity. In S. cerevisiae, Rad27Fen1 was suggested to protect against MMS-induced cytotoxicity by excising multinucleotide flaps generatedduringrepair.However,weproposedthattherepairintermediatewithablocked59-end,i.e.,59-dRPgroup,isthe actualcytotoxiclesion.Inprovidinga59-dRPgroupremovalfunctionmediatedbydRPlyaseactivityofPolb,theeffectsof the59-dRPgroupwereseparatedfromthoseofthemultinucleotideflapitself.HumanPolbwasexpressedinS.cerevisiae, andthispartiallyrescuedtheMMShypersensitivityobservedwithrad27fen1-nullcells.Toexplorethisrescueeffect,altered formsofPolbwithsite-directedeliminationsofeitherthe59-dRPlyaseorpolymeraseactivitywereexpressedinrad27fen1- nullcells.The59-dRPlyase,butnotthepolymeraseactivity,conferredtheresistancetoMMS.Theseresultssuggestthat afterMMSexposure,the59-dRPgroupintherepairintermediateiscytotoxicandthatRad27Fen1protectionagainstMMSin wild-typecellsisduetoeliminationofthe59-dRPgroup. Citation: Heacock M, Poltoratsky V, Prasad R, Wilson SH (2012) Evidence for Abasic Site Sugar Phosphate-Mediated Cytotoxicity in Alkylating Agent Treated Saccharomycescerevisiae.PLoSONE7(10):e47945.doi:10.1371/journal.pone.0047945 Editor:BeataG.Vertessy,InstituteofEnzymologyoftheHungarianAcademyofScience