Telomeres,whichdefinetheendsofchromosomes,consistofshort,tandemlyrepeatedDNAsequenceslooselyconservedineukaryotes.Telomeraseisaribonucleoproteincomplex(weonlyshowafewofthecomponentsinthisillustration)whichinvitrorecognizesasingle-strandedG-richtelomereprimerandaddsmultipletelomericrepeatstoits3-primeendbyusinganRNAtemplate.Telomerasemayalsohavearoleindenovoformationoftelomeres.Telomerasehasbeenidentifiedinmanyculturedcelllinesandactivelydividingcelltypes.TheactivereversetranscriptasecomponenthasbeenidentifiedintehTERTprotein.ThepresenceofthisfactordeterminestheavailABIlityofthetelomerasefunction.TheTERTproteinhasahighturnoverrateanditsexpressionisregulatedbyfactorsthatpromotegrowth(c-MYC,v-k-ras,Bcl-2andE6)andinhibitingfactors(RBandp53)thatpromotecelldeathorthatblockcelldivision.ItappearsthattheregulationofactivetelomerasehasmanylevelsandcanbeinhibitedbyTEP1notreleasingTERTorbyTRF1whichbindstheendrepeatsandpreventsaccesstothechromosomeends.AdditionalmodulationisduetophosphorlyationbyPKCandAKTordephophorylationbyPP2A.Wilkeetalfoundthatacaseofhumanalpha-thalassemiawascausedbyatruncationofchromosome16thathadbeenhealedbytheadditionoftelomericrepeats(TTAGGG)n.Humantelomeresconsistofmanykilobasesof(TTAGGG)ntogetherwithvariousassociatedproteins.SmallamountsoftheseterminalsequencesarelostfromthetipsofthechromosomesduringeachSphasebecauseofincompleteDNAreplication,butdenovoadditionofTTAGGGrepeatsbytheenzymetelomerasecompensatesforthisloss.Manyhumancellsprogressivelyloseterminalbaseswitheachcelldivision,alossthatcorrelateswiththeapparentabsenceoftelomeraseinthesecells.TherehasbeenconsiderableinterestinthepossIBLerelationshipbetweenhumantelomeresandcellularsenescenceandimmortalization.Thisinterestincludesthequestionofaroleinthemalignantprocessandthequestionoftheuseoftelomeraseinhibitorsasanti-tumordrugs.

Contributor:KosiGramatikoff,PhD

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