Both hMutSα and hMutS？ DNA Mismatch Repair Complexes Participate in 5-Fluorouracil Cytotoxicity 英文参考文献.docVIP

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Both hMutSα and hMutS？ DNA Mismatch Repair Complexes Participate in 5-Fluorouracil Cytotoxicity 英文参考文献.doc

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Both hMutSα and hMutS？ DNA Mismatch Repair Complexes Participate in 5-Fluorouracil Cytotoxicity 英文参考文献

BothhMutSaandhMutS?DNAMismatchRepair ComplexesParticipatein5-FluorouracilCytotoxicity AkihiroTajima2.,MoriyaIwaizumi1,2.,StephanieTseng-Rogenski1,BettyL.Cabrera2,JohnM. Carethers1,2,3 * 1DivisionofGastroenterology,DepartmentofInternalMedicine,UniversityofMichigan,AnnArbor,Michigan,UnitedStatesofAmerica,2DivisionofGastroenterology, DepartmentofMedicine,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,3MooresComprehensiveCancerCenter,UniversityofCalifornia SanDiego,LaJolla,California,UnitedStatesofAmerica Abstract Background: Patients with advanced microsatellite unstable colorectal cancers do not show a survival benefit from 5- fluorouracil(5-FU)-basedchemotherapy.WeandothershaveshownthattheDNAmismatchrepair(MMR)complexhMutSa binds5-FUincorporatedintoDNA.AlthoughhMutS?isknowntointeractwithinterstrandcrosslinks(ICLs)inducedbydrugs suchascisplatinandpsoralen,ithasnotbeendemonstratedtointeractwith5-FUincorporatedintoDNA.Ouraimwasto examineifhMutS?playsarolein5-FUrecognition. Methods:Wecomparedthenormalizedgrowthof5-FUtreatedcellscontainingeitherorbothmismatchrepaircomplexes using MTT and clonogenic assays. We utilized oligonucleotides containing 5-FU and purified baculovirus-synthesized hMutSaandhMutS?inelectromobilityshiftassays(EMSA)andfurtheranalyzedbindingusingsurfaceplasmonresonance. Results:MTTandclonogenicassaysafter5-FUtreatmentdemonstratedthemostcytotoxicityincellswithbothhMutSaand hMutS?,intermediatecytotoxicityincellswithhMutSaalone,andtheleastcytotoxicityincellswithhMutS?alone,hMutS? binds5-FU-modifiedDNA,butitsrelativebindingislessthanthebindingof5-FU-modifiedDNAbyhMutSa. Conclusion:Cytotoxicityinducedby5-FUisdependentonintactDNAMMR,withrelativecelldeathcorrelatingdirectlywith hMutSa and/or hMutS? 5-FU binding ability (hMutSa.hMutS?). The MMR complexes provide a hierarchical chemosensitivity for 5-FU cell death, and may have implications for treatment of patients with certain MMR-deficient tumors. Citation:TajimaA,IwaizumiM,Tsen