©HigherEducationPressandSpringer-VerlagBerlinHeidelberg2013May2013|Volume4|Issue5|325ProteinCell2013,4(5):325–330DOI10.1007/s13238-013-3001-5ProteinCell&ProteinCell&NuclearmicroRNAsandtheirunconventionalroleinregulatingnon-codingRNAsINI-REVIEWMHongweiLiang,JunfengZhang,KeZen,Chen-YuZhang,XiChenJiangsuEngineeringResearchCenterformicroRNABiologyandBiotechnology,StateKeyLaboratoryofPharmaceuticalBiotechnology,SchoolofLifeSciences,NanjingUniversity,Nanjing210093,ChinaCorrespondence:xichen@nju.edu.cn(X.Chen),cyzhang@nju.edu.cn(C.Zhang)ReceivedJanuary2,2013AcceptedFebruary22,2013ABSTRACTMicroRNAs(miRNAs)aresmallnon-codingRNAs(ncR-NAs)thatareinvolvedinpost-transcriptionalgeneregula-tion.IthaslongbeenassumedthatmiRNAsexerttheirrolesonlyinthecytoplasm,wheretheyrecognizetheirtargetprotein-codingmessengerRNAs(mRNAs),andresultintranslationalrepressionortargetmRNAdegrada-tion.Recentstudies,however,haverevealedthatmaturemiRNAscanalsobetransportedfromthecytoplasmtothenucleusandthatthesenuclearmiRNAscanfunctioninanunconventionalmannertoregulatethebiogenesisandfunctionsofncRNAs(includingmiRNAsandlongncRNAs),addinganewlayerofcomplexitytoourunder-standingofgeneregulation.Inthisreview,wesummarizerecentliteratureontheworkingmodeloftheseunconven-tionalmiRNAsandspeculateontheirbiologicalsignifi-cance.WehaveeveryreasontobelievethatthesenovelmodelsofmiRNAfunctionwillbecomeamajorresearchtopicingeneregulationineukaryotes.KEYWORDSmicroRNA,nuclearmicroRNA,non-codingRNA,nucleus,Argonaute,Exportin,ImportinINTRODUCTIONMicroRNAs(miRNAs)areaclassofnaturallyoccurring,single-stranded,small,non-codingRNAs(ncRNAs)of22nucleotidesinlengththatplaypivotalrolesinpost-transcriptionalgeneregulation(Ambros,2004;Bartel,2004).ResearchduringthepastdecadehasidentifiedmajorfactorsparticipatinginmiRNAbiogenesisandhasestablishedthebasicprinciplesofmiRNAfunction.Inconventionallinearprocessingpathways,anmiRNAgeneisfirsttranscribedbyRNApolymeraseIIorRNApolymeraseIIIintoaprimarymiRNAtranscript(pri-miRNA)(Ambros...