SHMT1 and SHMT2 Are Functionally Redundant in Nuclear De novo Thymidylate Biosynthesis 英文参考文献.docVIP

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SHMT1 and SHMT2 Are Functionally Redundant in Nuclear De novo Thymidylate Biosynthesis 英文参考文献.doc

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SHMT1 and SHMT2 Are Functionally Redundant in Nuclear De novo Thymidylate Biosynthesis 英文参考文献

SHMT1andSHMT2AreFunctionallyRedundantin NuclearDenovoThymidylateBiosynthesis DonaldD.Anderson1,PatrickJ.Stover1,2* 1GraduateFieldofBiochemistry,MolecularandCellularBiology,CornellUniversity,Ithaca,NewYork,UnitedStatesofAmerica,2DivisionofNutritionalSciences,Cornell University,Ithaca,NewYork,UnitedStatesofAmerica Abstract The three enzymes that constitute the de novo thymidylate synthesis pathway in mammals, cytoplasmic serine hydroxymethyltransferase(SHMT1),thymidylatesynthase(TYMS)anddihydrofolatereductase(DHFR)undergosumoylation andnuclearimportduringS-phase.Inthisstudy,wedemonstratethatpurifiedintactmouselivernucleiconvertdUMPto dTMP in the presence of NADPH and serine. Neither nuclear extracts nor intact nuclei exposed to aminomethylpho- sphonate,aSHMTinhibitor,exhibitthymidylatesynthesisactivity.NucleiisolatedfromShmt12/2mouseliversretained25% of thymidylate synthesis activity exhibited by nuclei isolated from wild type mice. This residual activity was due to the presence of a cytoplasmic/nuclear isozyme of SHMT encoded by Shmt2. Shmt2 is shown toencode two transcripts, one whichencodesaproteinthatlocalizesexclusivelytothemitochondria(SHMT2),andasecondtranscriptthatlacksexon1 andencodesaproteinthatlocalizestothecytoplasmandnucleusduringS-phase(SHMT2a).TheabilityofShmt2toencode acytoplasmicisozymeofSHMTmayaccountfortheviabilityofShmt12/2miceandprovideredundancythatpermittedthe expansionofthehumanSHMT1L474FpolymorphismthatimpairsSHMT1sumoylationandnucleartranslocation. Citation:AndersonDD,StoverPJ(2009)SHMT1andSHMT2AreFunctionallyRedundantinNuclearDenovoThymidylateBiosynthesis.PLoSONE4(6):e5839. doi:10.1371/journal.pone.0005839 Editor:MarceloBonini,NationalInstitutesofHealth(NIH)/NationalInstituteofEnvironmentalHealthSciences(NIEHS),UnitedStatesofAmerica ReceivedMarch15,2009;AcceptedApril30,2009;PublishedJune9,2009 Copyright:?2009Anderson,Stover.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermits unrestrictedus