Telomerase and Telomere-Associated Proteins tructural Insights into Mechanism and Evolution

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1、StructureReviewTelomeraseandTelomere-AssociatedProteins:StructuralInsightsintoMechanismandEvolutionKarenA.Lewis1andDeborahS.Wuttke1,*1DepartmentofChemistryandBiochemistry,UniversityofColoradoBoulder,Boulder,CO80309,USA*Correspondence:deborah.wuttke@colorado.eduDOI10.1016/j.str.2011.10.017R

2、ecentadvancesinourstructuralunderstandingoftelomeraseandtelomere-associatedproteinshavecontributedsignificantlytoelucidatingthemolecularmechanismsoftelomeremaintenance.ThestructuresoftelomeraseTERTdomainshaveprovidedvaluableinsightsintohowexperimentallyidentifiedconservedmotifscontributetoth

3、etelomerasereversetranscriptasereaction.Additionally,structuresoftelomere-associatedproteinsinavarietyoforganismshaverevealedthat,acrossevolution,telomere-maintenancemechanismsemploycommonstructuralelements.Forexample,thesingle-stranded30overhangoftelomericDNAisspecificallyandtightlyboundby

4、anOB-foldinnearlyallspecies,includingciliates(TEBPandPot1a),fissionyeast(SpPot1),buddingyeast(Cdc13),andhumans(hPOT1).StructuresoftheyeastCdc13,Stn1,andTen1proteinsdemonstratedthattelomeremaintenanceisregulatedbyacomplexthatbearssignificantsimilaritytotheRPAheterotrimer.Similarly,proteinstha

5、tspecificallybinddouble-strandedtelomericDNAindivergentspeciesusehomeodomainstoexecutetheirfunctions(humanTRF1andTRF2andbuddingyeastScRap1).Likewise,theconservedproteinRap1,whichisfoundinbuddingyeast,fissionyeast,andhumans,containsastructuralmotifthatisknowntobecriticalforprotein-proteininte

6、raction.Inadditiontorevealingthecommonunderlyingthemesoftelomeremaintenance,structureshavealsoelucidatedthespecificmechanismsbywhichmanyoftheseproteinsfunction,includingidentifyingatelomere-specificdomaininStn1andhowthehumanTRFproteinsavoidheterodimerization.Inthisreview,wesummarizethehigh-r

7、esolutionstructuresoftelomeraseandtelomere-associatedproteinsanddiscusstheemergentcommonstructuralthemesamongtheseproteins.Wealsoaddresshowthesehigh-resolutionstructurescomplementbiochemicalandcellularstudiestoenhanceourunderstandingoftelomeremaintenanceandfun