MiRNATargeting–GrowingBeyondtheSeedLauraB.Chipman,AmyE.Pasquinelli*DivisionofBiology,UniversityofCalifornia,SanDiego,LaJolla,CA92093-0349,USA.AbstractMicroRNAs(miRNAs)aresmallRNAsthatguideArgonaute(AGO)proteinstospecifictargetmessengerRNAs(mRNAs)torepresstheirtranslationandstability.Canonically,miRNAtargetingisreliantonbasepairingoftheseedregion,nucleotides(nts)2–7,ofthemiRNAtositesinmRNA3’UTRs.Recently,the3’halfofthemiRNAhasgainedattentionfornewlyappreciatedrolesinregulatingtargetspecificityandregulation.Additionally,theextentofpairingtothemiRNA3’-endcaninfluencethestabilityofthemiRNAitself.ThesefindingshighlighttheimportanceofsequencesbeyondtheseedincontrollingthefunctionandexistenceofmiRNAs.KeywordsmicroRNA;miRNAtargeting;seedpairing;miRNAfamilyTargetrecognitionandregulationbymiRNAsSincetheirdiscoveryintheearly1990s[1,2],thousandsofmicroRNAs(miRNAs)havebeenidentifiedacrosstheplantandanimalkingdoms[3].ThereisnowevidencethatmiRNAsimpacteverymajorbiologicalpathwaybyregulatingtheexpressionofsubstantialfractionsofprotein-codinggenes[4,5].Giventhisomnipresentroleingeneregulation,itisnotsurprisingthatmisregulationofindividualmiRNAscanhavedireconsequences,contributingtoavarietyofdiseasesandafflictionsinhumans[6].WithinthemiRNAinducedsilencingcomplex(miRISC)(seeGlossary),the~22nucleotide(nt)miRNArecruitsArgonaute(AGO)tospecifictargetsitesviabase-pairinginteractions[4,7].Perfectbase-pairingofthemiRNAwithitstargetsite,whichiscommoninplantsbutrareinanimals,resultsinendonucleolyticcleavagebyAGOofthetargetRNA.AnimalmiRNAstypicallyformapartialduplexwiththeirtargetsite,whichpreventscleavageandinsteadreliesonAGOco-factorstoregulatetargetexpressionthroughtranslationalrepressionandmRNAdestabilization[4,7].Pairingofnucleotides(nts)2–7ofthemiRNA,calledtheseed,toitstargetsitehasgenerallybeenconsideredtheminimalelementneededtoengageatargetmRNA[4].Indeed,structuralstudieshaveshownthatonlysequenceswithintheseedoftheAGO-boundmiRNAareavailableforinitialpairingtoatargetsite[8–10]....
