ArticleTheU6snRNAm6AMethyltransferaseMETTL16RegulatesSAMSynthetaseIntronRetentionGraphicalAbstractHighlightsdIntronretentionoftheSAMsynthetaseMAT2ARNAisresponsivetoSAMlevelsdMETTL16andhp1arerequiredforinductionofMAT2AsplicingdOccupancyofMETTL16onhp1promotessplicingoftheMAT2AretainedintrondMETTL16m6AmethylatesMAT2AhairpinsandthespliceosomalU6snRNAAuthorsKathrynE.Pendleton,BeibeiChen,KuanqingLiu,OlgaV.Hunter,YangXie,BenjaminP.Tu,NicholasK.ConradCorrespondencenicholas.conrad@utsouthwestern.eduInBriefAnRNAmethyltransferasecontrolscellularSAMlevelsthroughpost-transcriptionalregulatoryfeedback.Pendletonetal.,2017,Cell169,824–835May18,2017ª2017ElsevierInc.http://dx.doi.org/10.1016/j.cell.2017.05.003ArticleTheU6snRNAm6AMethyltransferaseMETTL16RegulatesSAMSynthetaseIntronRetentionKathrynE.Pendleton,1BeibeiChen,2KuanqingLiu,3OlgaV.Hunter,1YangXie,2BenjaminP.Tu,3andNicholasK.Conrad1,4,*1DepartmentofMicrobiology2DepartmentofClinicalSciences3DepartmentofBiochemistryUTSouthwesternMedicalCenter,Dallas,TX75390,USA4LeadContact*Correspondence:nicholas.conrad@utsouthwestern.eduhttp://dx.doi.org/10.1016/j.cell.2017.05.003SUMMARYMaintenanceofproperlevelsofthemethyldonorS-adenosylmethionine(SAM)iscriticalforawidevarietyofbiologicalprocesses.WedemonstratethattheN6-adenosinemethyltransferaseMETTL16regulatesexpressionofhumanMAT2A,whichen-codestheSAMsynthetaseexpressedinmostcells.UponSAMdepletionbymethioninestarvation,cellsinduceMAT2Aexpressionbyenhancedsplicingofaretainedintron.InductionrequiresMETTL16anditsmethylationsubstrate,avertebrateconservedhairpin(hp1)intheMAT2A30UTR.IncreasingMETTL16occupancyontheMAT2A30UTRissuffi-cienttoinduceefficientsplicing.Weproposethat,underSAM-limitingconditions,METTL16occupancyonhp1increasesduetoinefficientenzymaticturn-over,whichpromotesMAT2Asplicing.WefurthershowthatMETTL16isthelong-unknownmethyl-transferasefortheU6spliceosomalsmallnuclearRNA(snRNA).TheseobservationssuggestthattheconservedU6snRNAmethyltransferaseevolvedanadditionalfunctioninvertebrat...
