Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil.docVIP

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Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil.doc

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Base Excision by Thymine DNA Glycosylase Mediates DNA-Directed Cytotoxicity of 5-Fluorouracil

o PL SBIOLOGY BaseExcisionbyThymineDNAGlycosylase MediatesDNA-DirectedCytotoxicity of5-Fluorouracil Christophe Kunz1,Frauke Focke1,Yusuke Saito1,David Schuermann1,Teresa Lettieri2,Jim Selfridge3,Primo Scha¨r1* 1 Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland, 2 Institute of Cell Biology, ETH Zu¨rich, Zu¨rich, Switzerland, 3WellcomeTrustCentreforCellBiology,InstituteofCellandMolecularBiology,UniversityofEdinburgh,Edinburgh,Scotland 5-Fluorouracil (5-FU), a chemotherapeutic drug commonly used in cancer treatment, imbalances nucleotide pools, therebyfavoringmisincorporationofuraciland5-FUintogenomicDNA.TheprocessingofthesebasesbyDNArepair activitieswasproposedtocauseDNA-directedcytotoxicity,buttheunderlyingmechanismshavenotbeenresolved.In this study, we investigated a possible role of thymine DNA glycosylase (TDG), one of four mammalian uracil DNA glycosylases(UDGs),inthecellularresponseto5-FU.Usinggeneticandbiochemicaltools,wefoundthatinactivation ofTDGsignificantlyincreasesresistanceofbothmouseandhumancancercellstowards5-FU.Weshowthatexcisionof DNA-incorporated 5-FU by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNAdamagesignaling,andthattherepairof5-FU–inducedDNAstrandbreaksismoreefficientintheabsenceofTDG. Hence,excisionof5-FUbyTDG,butnotbyotherUDGs(UNG2andSMUG1),preventsefficientdownstreamprocessing oftherepairintermediate,therebymediatingDNA-directedcytotoxicity.ThestatusofTDGexpressioninacanceris thereforelikelytodetermineitsresponseto5-FU–basedchemotherapy. Citation:KunzC,FockeF,SaitoY,SchuermannD,LettieriT,etal.(2009)BaseexcisionbythymineDNAglycosylasemediatesDNA-directedcytotoxicityof5-fluorouracil.PLoS Biol7(4):e1000091.doi:10.1371/journal.pbio.1000091 associated uracil DNA glycosylase (UDG) UNG2 connected with futile cycles of base excision repair (BER) [2,10,11]. Introduction The antimetabolite 5-?uorouracil (5-FU) is an analog of uracil with a ?uorine