TheU6snRNAm6AmethyltransferaseMETTL16regulatesSAMsynthetaseintronretentionKathrynE.Pendleton1,BeibeiChen2,KuanqingLiu3,OlgaV.Hunter1,YangXie2,BenjaminP.Tu3,andNicholasK.Conrad1,*1DepartmentofMicrobiology,UTSouthwesternMedicalCenter,DallasTX753902DepartmentofClinicalSciences,UTSouthwesternMedicalCenter,DallasTX753903DepartmentofBiochemistry,UTSouthwesternMedicalCenter,DallasTX75390SUMMARYMaintenanceofproperlevelsofthemethyldonorS-adenosylmethionine(SAM)iscriticalforawidevarietyofbiologicalprocesses.WedemonstratethattheN6-adenosinemethyltransferaseMETTL16regulatesexpressionofhumanMAT2A,whichencodestheSAMsynthetaseexpressedinmostcells.UponSAMdepletionbymethioninestarvation,cellsinduceMAT2Aexpressionbyenhancedsplicingofaretainedintron.InductionrequiresMETTL16anditsmethylationsubstrate,avertebrateconservedhairpin(hp1)intheMAT2A3´UTR.IncreasingMETTL16occupancyontheMAT2A3´UTRissufficienttoinduceefficientsplicing.WeproposethatunderSAM-limitingconditions,METTL16occupancyonhp1increasesduetoinefficientenzymaticturnover,whichpromotesMAT2Asplicing.WefurthershowthatMETTL16isthelong-unknownmethyltransferasefortheU6spliceosomalsnRNA.TheseobservationssuggestthattheconservedU6snRNAmethyltransferaseevolvedanadditionalfunctioninvertebratestoregulateSAMhomeostasis.Graphicalabstract*CorrespondingAuthorandLeadContact:Nicholas.conrad@utsouthwestern.edu.Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaservicetoourcustomersweareprovidingthisearlyversionofthemanuscript.Themanuscriptwillundergocopyediting,typesetting,andreviewoftheresultingproofbeforeitispublishedinitsfinalcitableform.Pleasenotethatduringtheproductionprocesserrorsmaybediscoveredwhichcouldaffectthecontent,andalllegaldisclaimersthatapplytothejournalpertain.AUTHORCONTRIBUTIONSConceptualization,N.K.C.andK.E.P.;Methodology,K.E.P.,B.C.,K.L.,O.V.H.,B.P.T.,N.K.C.;Investigation,K.E.P.,B.C.,K.L.,O.V.H.,N.K.C.;DataCuration,K.E.P,B.C.;Writing—originaldraft,K.E.P.andN.K.C.;Writing—Review...
