Therelationshipbetweentelomeraseenzymeactivityandtelomerelengthisnotonlycriticalforcellularaginganddisease,butalsorepresentsaprimetherapeutictargetforthe
treatmentofcancer.[iStock/?ttsz]
Recentprogressintelomereresearchthroughnewtoolsandassaysmayallowinvestigatorstodelvemoredeeplyintothecomplicatedmechanismsthatcontrol
thesekeychromosomalstructures.
AsdescribedbyXinetal.,inGenomeBiologyin2008,telomeresarenucleoproteinstructuresattheendsofeukaryoticchromosomes.Thesestructureshelp
maintaineukaryoticgenomeintegritybypreventingchromosomalrearrangementsorchromosomesfusingtoeachother,andbyenablingcompletereplicationofthe
endsofthelinearDNAmolecules.
TelomericDNAiscomposedofaseriesofsequencerepeatsandterminatesina3′single-stranded(ss)DNAoverhang.AteachroundofDNAreplicationthe
telomericDNAbecomesshorter,butcanberegeneratedbytheenzymetelomerase,anRNA-containingDNApolymerase.Telomeresandtelomeraseplaykey
rolesinmaintainingchromosomeintegrityintheagingprocess,andincancer.
Telomerasebalancesthetelomereshorteningthatoccursduringcelldivisionbyaddingtelomererepeatsontochromosomeends.Whiletheenzymeexistsatvery
loworundetectablelevelsinnormalsomaticcells,itiscontinuouslyexpressedin80-95%oftumors,actingtocontinuouslyelongatetelomeresandconferringasort
ofimmortalityontherapidlydividingcells.
Innormalcells,aseriesoffeedbackmechanismsmaintainsthebalancebetweenshorteningandlengtheningestablisheddynamictelomerelengthequilibriumin
humans.
Inrecognitionofthisstructure’scriticalfunctions,ElizabethBlackburn,Ph.D.,UniversityofCalifornia,SanFrancisco,andcolleaguesJackSzostakPh.D.,of
HowardHughesMedicalInstitute,andCarolGreider,Ph.D.,ofJohnsHopkinsUniversity,receivedthe2009NobelPrizeinPhysiologyandMedicine.
Theawardcitedthescientists’workontelomeresandforidentifyingthetelomeraseenzyme,inadditiontothe“discoveryofafundamentalmechanisminthecell—a
discoverythathas“stimulatedthedevelopmentofnewtherapeuticstrategies”,accordingtotheNobelPrizecommittee.
Now,recentresearchbyDr.GreiderandhercolleaguesatJohnsHopkinsUniversity,reportedintheNovember24,2015,issueofjournalCellReports,detailsthe
developmentoftheADDITassaytomeasurenewtelomereadditionatasingletelomereinvivo.Thisdiscoveryhasgreatlyfacilitatedthedetectionandstudyof
telomericlength,whichpriortothedevelopmentofthisnovelassaytookmonthsofwork.
Becauseoftheirrolesinhumanagingandtheirassociationwithmalignancy,telomeresandtelomerasehavebecomethefocusofdrugdiscoveryresearchto
potentiallyinterveneintheagingprocess,andtotreatdiseasescausedbydysregulatedtelomericshorteningandcancer.
IncommentingonthefieldingeneralinaninterviewinNature,Dr.Greider’sco-NobellaureateDr.Blackburnsaid“Wehaveapartslist,soweknowwhat(the
telomere)doesinastaticsense.Butinlivecells,telomeresareextraordinarilydynamic…complexlittleecosystemsthatconstantlyhaveproteinsarrivingand
leavingeverysecond.Ithinkwecouldlearnahugeamountbystudyingtelomeresinaction,ratherlikeresearchersdobywatchingactiveribosomesassemble
proteins,inadditiontoknowingtheirstructure.”
GENExclusives
Dec16,2015
TelomeresRule
KeyDNAElementsforReplicationbutTrickyDrugTargetsPatriciaFitzpatrickDimond,Ph.D.
HowTelomeresWork
TelomeresconsistofDNAcharacterizedbynoncodingrepetitivesequencesandmultipleproteincomponents.Repeatsequencesvaryfromonespeciestothe
other,thesix-nucleotiderepeatTTAGGGbeingcharacteristicofhumansandothervertebrates.Atthe3′endoftelomeres,asingleDNAstrandofabout300
nucleotidesloopsbackwithsomeofthedouble-strandedDNAformingthe“Tloop”thatplaysaprotectiverolebysequesteringtheoverhangterminalinsidethe
doublestrand.Asix-proteincomplex,theshelterincomplex,functionstomaintaintelomerelength,promoteTloopformation,recruittelomerasetotelomericends,
andprotectchromosomeendsfrombeingdetectedasDNAdamage.
Inhumans,syndromesoftelomereshorteningcauseage-relateddegenerativediseasesincludingdyskeratosiscongenita,pulmonaryfibrosis,aplasticanemia,and
others.Incellslackingtelomerase,telomeresshortenwitheachcelldivisionduetoincompletereplicationofthelaggingstrand,oxidativedamage,andtelomere
processingevents.Telomeresalsoshortennormallywithaging
Telomeraseactivityisnotdetectedinmostsomaticcellsbutisnearlyuniversallyactiveinhumancancercelllinesandinmostprimarytumors.Telomeraseactivity
counteractsprogressivetelomereshorteningduringcellularreplicationbysynthesizingnewtelomericDNArepeatsatthechromosomaltermini.Thehuman
telomeraseholoenzymecorecomponentsincludeacatalyticreversetranscriptase,hTERT(humantelomerasereversetranscriptase),andanassociatedtemplate
RNA,hTERC(humanTelomeraseRNA).hTERCisubiquitouslyexpressedinallhumancells,andtelomeraseactivityislimitedbytheexpressionofhTERT,which
isfoundonlyincellswithdetectabletelomeraseactivity.
Telomeresshortenwitheachroundofcelldivision,amechanismthatlimitsproliferationofhumancellstoafinitenumberofcelldivisionsbyinducingreplicative
senescence,differentiation,orapoptosis.Telomereshorteningcanactasatumorsuppressor,butasJiang,ZZhu,andKLRudolphnotedintheirarticleinthe
October,2007issueofZeitschriftfürGerontologieundGeriatrie,the“downside”ofthisideaisthataccumulatingevidenceindicatesthattelomereshorteningalso
limitsstemcellfunction,regeneration,andorganmaintenanceduringaging.Andtelomereshorteningduringaginganddiseaseisassociatedwithincreasing
cancerrisk.
DavidR.Corey,Ph.D.,ofUniversityofTexasSouthwesternMedicalCenter,writinginChemicalBiologyin2009,saidthatseveralobstacleshaveparticularly
impededdevelopmentoftelomeraseinhibitors,includinglackofpurifiedhumantelomeraseinsufficientquantitiestoallowinhibitorscreening.Untilrecently,hesaid,
nohigh-resolutionstructuralinformationabouttheenzymewasavailable,complicatingstructure-baseddesignstrategies.Andsincetelomeraseisapolymerase,
inhibitorswouldneedtobeselectiveforitsinhibitionrelativetoothercellularpolymerases.
Becauseofitspivotalroleinagingandcancer,theenzymetelomerasehasnonethelessbecomethefocusofdrugdevelopmenteffortsforanticancertherapeutics,
thegoalbeinginhibitionoftelomerase,leadingtoadecreaseoftelomerelength,resultingincellsenescenceandapoptosisintelomerase-positivetumors.
Approachestotelomeraseinhibitionhaveincludedsmallmoleculeinhibitors,antisenseoligonucleotides,immunotherapies,andgenetherapiesthattargetthe
hTERTortheribonucleoproteinsubunit,aswellanautologoushTERT-pulseddendriticcell-basedvaccineunderdevelopmentbyBioTimesubsidiaryAsterias.
Asterias’AST-VAC1andAST-VAC2aredendriticcell-basedvaccinesdesignedtoimmunizecancerpatientsagainsttelomerase.AST-VAC2differsfromAST-
VAC1inthatthedendriticcellspresentingtelomerasetotheimmunesystemareproducedfromhumanembryonicstemcellsinsteadofbeingderivedfromhuman
blood.
Geron’sImetelstat,alipid-conjugated13-meroligonucleotidesequencecomplementarytotheRNAtemplateofthetelomerase,directlyinhibitstheenzyme’s
activity.GeronhaspartneredwithJanssenBiotechtodevelopandcommercializeImetelstatworldwideforallindicationsinoncology,includinghematologicmyeloid
malignancies,andallotherhumantherapeuticuses.Underthecollaborationagreement,Janssenisresponsibleforthedevelopment,manufacturing,and
commercializationofImetelstatworldwide.OnSeptember16,2015,GeronannouncedthedosingofthefirstpatientinaPhaseIItrialtoevaluateImetelstatin
patientswithmyelofibrosis.
InarecentlypublishedNewEnglandJournalofMedicinepaperbyGabrielaM.Baerlocher,M.D.andcolleagues,itwasreportedthatImetelstatshoweddisease-
modifyingactivityinPhaseIIstudiesofmyelofibrosisandessentialthrombocythemia.Amongthrombocythemiapatients,patientsachievedahematologicresponse,
withthemajorityachievingahematologiccompleteresponse.
InthesecondpaperauthoredbyAyalewTefferi,M.D.,etal.,theinvestigatorsfoundthatImetelstatwasactiveinpatientswithmyelofibrosisbutalsohadthe
potentialtocauseclinicallysignificantmyelosuppression.
Inthelongrun,thetherapeuticeffectsofanydrugsthantargettelomerasewillnodoubtneedtobeweighedagainsttheirsideeffectsandthefullimplicationsofits
ubiquitousroleduringnormalcellDNAreplicationinrapidlyrenewingcellpopulations.
ToenjoymorearticleslikethisfromGEN,clickheretosubscribenow!
|
|
