CLINICALu998

HigherEducationPressandSpringer-VerlagBerlinHeidelberg2013August2013|Volume4|Issue8|573ProteinCell2013,4(8):573–581DOI10.
1007/s13238-013-3002-4ProteinCell&ProteinCell&*Theseauthorscontributedequallytothework.
Howwilltelomericcomplexbefurthercontributedtoourlongevity—ThepotentialnovelbiomarkersoftelomerecomplexcounteractingbothagingandcancerYimingLu1*,BohuaWei1*,TaoZhang2,ZiChen3,JingYe1,41ShanghaiRuijinHospital,ShanghaiJiaotongUniversitySchoolofMedicine,Shanghai200025,China2DepartmentofLaboratoryMedicine,HuashanHospital,FudanUniversity,Shanghai200040,China3DepartmentofHematology,HuashanHospital,FudanUniversity,Shanghai200040,China4UniversityofNice,LaboratoryofBiologyandPathologyofGenomes,UMR6267,CNRSU998,INSERM28avenue,ValombroseFacultédeMédecine06107,NiceCedex2,FranceCorrespondence:drchenzi@tom.
com(Z.
Chen),yj11254@rjh.
com.
cn(J.
Ye)ReceivedJanuary10,2013AcceptedMarch27,2013ABSTRACTWiththesmoothmovetowardsthecomingexpectedclinicalreportsofanticancerpharmaceuticalmoleculestargetingtelomeresandtelomerase,andalsowiththeex-citingsuccessintheextensionoflifespanbyregulatingtelomeraseactivitywithoutincreasedonsetofoncogen-esisinlaboratorymousemodels(Garcia-Caoetal.
,2006;Jaskelioffetal.
,2011),weareconvincedthattargetingtelomeresbasedontelomerasewillbeapotentialap-proachtoconquerbothagingandcancerandtheideaoflongevityseemstobenomoremysterious.
Moreinterest-ingly,emergingevidencesfromclinicalresearchrevealthatothertelomericfactors,likespecictelomericbindingproteinsandnonspecifictelomereassociatedproteinsalsoshowcrucialimportanceinagingandoncogenesis.
ThisstemsfromtheirrolesinthestabilityoftelomerestructureandintheinhibitionofDNAdamageresponseattelomeres.
Uncappingtheseproteinsfromchromo-someendsleadstodramatictelomerelossandtelomeredysfunctionwhichismoreabruptthanthoseinducedbytelomeraseinactivation.
Abnormalexpressionofthesefactorsresultsindevelopmentalfailure,agingandevenoncogenesisevidencedbyseveralexperimentalmodelsandclinicalcases,indicatingtelomerespecicproteinsanditsassociatedproteinshavecomplimentaryrolestotelomeraseintelomereprotectionandcontrollingcellu-larfate.
Thus,thesetelomericfactorsmightbepotentialclinicalbiomarkersforearlydetectionoreventherapeutictargetsofagingandcancer.
Futurestudiestoelucidatehowtheseproteinsfunctionintelomereprotectionmightbenefitpatientssufferingagingorcancerwhoarenotsensitivetotelomerasemediation.
KEYWORDStelomere,telomerase,oncogenesis,senes-cence,telomerebindingproteinINTRODUCTIONOwingtothecontributionoftelomereandtelomerasestudyinthemedicaldevelopmentoflongevity,thescienticpioneerswhodiscoveredtelomerasehavebeenawardedtheNobelPrizein2009.
Thebeginningoftelomerestudycanbedatedbackto1960s,andtheresearchontelomeresandtelomerasesincethepastdecadesrevealswhywehavealimitedlifeandshedlightonhowwecanimproveourlifespan(BernardesdeJesusandBlasco,2000;Jaskelioffetal.
,2011;GunesandRu-dolph,2013)(Fig.
1).
HOWTOEXPANDLIFESPANBYTARGETINGTELOMERASEIneukaryoticcells,telomeresaregeneticcodeofrepeatedTTAGGGsequencesatlinealchromosomeendstoprotectgenomeintegrity.
TelomerefunctionisregulatedbytelomereEVIEWRYimingLuetal.
574|August2013|Volume4|Issue8HigherEducationPressandSpringer-VerlagBerlinHeidelberg2013ProteinCell&REVIEWandmalignantinltration.
Telomeraseactivityisindispensibleforthereproductionofstemcell,germlinecellsandhighproliferativecell(Leeetal.
,1998).
MousemodelsowingtothetelomeraseRNAde-ciencyresultinprematureaging(Blascoetal.
,1997).
TheseTR/miceshowedwiderangeofdegenerativepathologiesanddecreasedlongevityintheirlatergenerationduetocriticalshorttelomeresandchromosomeinstability.
Thesedegenera-tivediseasesincludeaplasticanemia,lungbrosis,xerodermapigmentosum,intestinalatrophy,germlinedepletionandhighincidenceofoncogenesis,etc.
(Rudolphetal.
,1999).
ClinicalstudyalsoidentiedreducedhTERTlevelormutatedhTERTinpatientswithdyskeratosiscongenita(DKC)(ShayandWright,2004).
Alltheseindicatethattelomeraseinducedtel-omereelongationisanessentialstepfortissuedevelopmentandrenewalcapacityandtelomerasereactivationissupposedtobeapossiblestrategytoreversephysiologicalaging.
In-deed,exogenousreplenishmentoftelomeraseisapossibletherapeuticstrategytocounteracttelomereassociateddegen-erativediseaseandreversephysiologicalaging(Garcia-Caoetal.
,2006;Jaskelioffetal.
,2011).
Telomeraseiscrucialfortumorprogression.
Experimentshaveshownthatover-expressionofexogenoushTERTinnor-malprimarybroblastcellsresultsinimmortalization.
Telom-erasereactivationintransformedcellsacceleratesmalignantprogressionandinltration.
Theproliferationofmalignanttrans-formedcellsduetocriticalshorttelomerescanberepressedintelomerasenegativecells,butacceleratedwhentelomeraseisreactivated(Bodnaretal.
,1998;Segeretal.
,2002).
Indeed,lengthandtelomerestructure.
Duetothereplicativeprob-lems,telomeresshortenduringeachcelldivision.
After40–80doublingpopulations,telomeresreachacriticallength,andtelomeredysfunctionexposesthenaturalchromosomeendstotheDNAdamageresponse(DDR)machinery.
Theactiva-tionofDDRrecruitsγH2AXand53BP1,thekeytransducersoftheDNAdamagecheckpointtoformfociattelomeres,whichiscalledtelomeredysfunctionfoci(TIF)(GilsonandSegal-Bendirdjian,2010;Yeetal.
,2010b).
Theyactivatedownstreamcheckpointkinasestoinducegrowtharrest,apoptosisandreplicativesenescence(d′AddadiFagagnaetal.
,2003).
Thus,theprotectivefunctionoftelomeresislimitedbythenumberofcellularpassageandtheinitialtelomerelengthisabiomedicalutensiltopredicttheindividual'snaturelongevity(Fig.
2).
Accumulationofshorttelomeresanddysfunctionaltelom-eresduetotheincreasedageresultinstemcelldysfunctionandtissuedegenerationduetothereplicativesenescenceincellswithnormalcheckpointactivationsystem(Rudolphetal.
,1999).
Incheckpointdecientcells,criticalshorttelomeresinducedtelomeredysfunctionresultsintumorigensis(Chinetal.
,1999;Artandietal.
,2000).
Hence,telomerestransmitthecrosstalkbetweenagingandcancer,andthiscouldexplainwhymosttypesofcancersareregardedasagingassociateddiseasestoacertainextent.
Telomerase,aribonucleaseenzyme,containsareversetranscriptase(hTERT),whichcatalyzesitsownRNAcom-ponentastemplatetoelongateshorttelomeresatacertainlength(GreiderandBlackburn,1985).
Liketelomerelength,telomeraseactivityisalsocrucialforbothtissueregenerationTelomerasereactivationShelterincomplexTelomereassociatedproteinsMaintenanceoftelomerestructure/functionExtendingtelomerelengthAnti-agingtherapyTissueregenerationReliefofprematureagingsyndromeanddevelopmentalabnormalityAnticancerLongevityFigure1.
Theroleoftelomericnucleocomplexinlongevity.
ThepotentialnovelbiomarkersoftelomerecomplexinagingandcancerHigherEducationPressandSpringer-VerlagBerlinHeidelberg2013August2013|Volume4|Issue8|575ProteinCell&REVIEWsyndromeandagingassociateddiseases,butalsosupporttheideathatextendinghealth-spanmightbenomoreafancy.
Thenovelanticancerdrugstargetingtelomerasewithdifferentpharmaceuticalprincipleshavealreadyenteredclinicalstudy.
Forexample,thesmallmoleculehTERTinhibitorBIBR1532andGRN163L,athio-phosphoramidateoligonucleotidetarget-ingthetemplateregionofhTRasa"templateantagonist"andGV1001,atelomerase-specic,promiscuousclassIIpeptidevaccinearecurrentlyinanadvancedstageofclinicaldevelop-ment(Shawetal.
,2010;Schlapbachetal.
,2011).
Moreimpor-tantly,mousemodelswiththecombinationofoverexpressionofTERTandtumorsuppressorgenes(Sp53/Sp16SARF/Tg-TERT)issupposedtodelayaging,extendmicelongevityandberesistanttooncogenesis,indicatingmediationoftelomeraseisakeypointforgenotherapyoflongevity(Garcia-Caoetal.
,2006;Jaskelioffetal.
,2011).
TELOMERESPECIFICBINDINGPROTEINSEMERGEASNOVELHALLMARKERSINAGINGRELATEDDISEASESANDAREPOTENTIALCANDIDATESFORCLINICALTREATMENTINTELOMEREDYSFUNCTIONINDUCEDDISEASESBesidesthegradualtelomerelossinsystematicorganismaltelomeraseisreactivatedin85%–95%oftumorcellsandclini-caladvancedcancertissues,butitisundetectableinnormalsomaticcells(Kimetal.
,1994;Wrightetal.
,1996).
hTERTpromotermutationfurtherprohibittelomerefunctionandisre-sponsibleforcertaincancermobidity(Hornetal.
,2013;Huangetal.
,2013).
Telomericrepeatamplicationprotocol(TRAP)assayisasensitiveandspecicmethodtodetecttelomeraseactivityinculturedcellsandclinicaltissuesamples,whichfa-cilitatesthetranslationoftelomerasestudyfromlabtobedside(Wrightetal.
,1995).
Telomeraseactivityissupposedtobeahope-fulmedicalbiomarkerforthesurveillanceofadvancedtumor.
Insummary,telomerelossisratelimitingfornaturelongev-ity.
Telomereshorteninginducedbytelomeraseinactivationisimplicatedinthereplicativesenescenceinducedrenewalinabilityofstemcellsorregenerationfailureofhighprolifera-tiveorgans,andtelomerasereactivationintelomeredysfunc-tioncellsfacilitatesmalignantproliferation.
Thus,biomedicalresearchtargetingtelomerasecouldbeadouble-edgedswordforbothanti-senescenttherapyandanticancertherapy.
In-deed,thefactthatpathologicalagingintelomerasedecientmicecanbereversedwithtelomerasereactivation,stronglyencouragesthefurtherstudyontelomerasebaseddrugdevel-opment(Garcia-Caoetal.
,2006;Jaskelioffetal.
,2011).
ThiswillnotonlygivehopetothetreatmentofcongenitalpresagingFigure2.
Causesandconsequencesoftelomeredysfunction.
TelomerasereactivationNormaltelomericstructureProgressivetelomerelossSuddentelomerelossandtelomericstructurecollapseγH2AXDDRATM/ATRActivationofNHEJTelomerefusionUnknownpathwayHomologousrecombination(T-toopHR,Sisterchromaticexchange)DysfunctionofshelterinandassociatedfactorsYimingLuetal.
576|August2013|Volume4|Issue8HigherEducationPressandSpringer-VerlagBerlinHeidelberg2013ProteinCell&REVIEWeresfrombeingrecognizedbyDNAdamageresponse.
TheyplayanimportantroleintheinhibitionofATMorATRactivationattelomeres,whichcanphosphatethedownstreamChk1andChk2andnallyblockcellcycledivision(Karlsederetal.
,1999,2004;DenchianddeLange,2007).
ShelterinalsorepressesDNArepairmachinery,includingnon-homologousendingjoin-ing(NHEJ),homologousrecombination(HR)andotherrepairpathway.
TheserepairmachineriesinTRF2compromisedcellsresultinchromosomeendfusion,telomeresisterchromatidexchangeandt-loopHRwhichthreatentelomereintegrity(vanSteenseletal.
,1998;Karlsederetal.
,1999;Smogorzewskaetal.
,2002)(Fig.
2).
Invivoevidencesalsodemonstratethatshelterinproteinsarephysiologicalelementsessentialforthemammaliandevel-opmentandtissuefunction.
TRF2knockoutmiceareembry-oniclethal.
TRF1,TPP1andRAP1conditionalknockoutmiceshowpresagingsyndromeandhighincidenceofoncogenesis(Martinezetal.
,2009,2010).
POT1deletioninducesmouseDKC(Hockemeyeretal.
,2008).
Theseknockoutmicedisplayabnormalsyndromeeveninnormaltelomerelength,whichindicatesthatindividualswithtelomeredysfunctioninducedbythedepletionofshelterincomponentsmightexhibitmoresevereandrapidpathologicalagingphenotypesthanthoseinducedbytelomerasedeciency.
Inconsistencewithmousemodels,geneticvariationinshelterincomponentshasbeenobservedinpatientswithcancerandpathologicalaging.
OneSNPofTRF1geneissignicantlyassociatedwithmelanoma,andmutatedTRF1allelehasbeenobservedinaplasticane-mia.
TIN2mutationshavebeenfoundinDKCpatients(Walneetal.
,2008;Sasaetal.
,2012).
Thereisnoreportonpatho-aging,telomeresequencehasbeenfoundlostdramaticallyindependentofreplicativetelomeredynamics(Karlsederetal.
,2002).
Thisisduetothedysfunctionoftelomerebindingproteins,whichbindspecictochromosomeendstocapthetelomericfragilestructure(vanSteenseletal.
,1998).
ThesetelomerecappingproteinsincludeTRF1,TRF2,POT1,TIN2,TPP1andRAP1.
Theyformaproteincomplexandalsoknownasshelterin/telosome(deLange,2005;Xinetal.
,2008)(Fig.
3).
Shelterinisinvolvedinthemaintenanceoftelomerelengthandtelomerestructure.
TRF1andTRF2bindtothedoublestrandoftelomeres,whereasPOT1bindstothesinglestrandoftelomeres.
Theynegativelyregulatetelomerelength(PalmanddeLange,2008).
TRF2isinvolvedintheorganizationoft-loop,aduplexlariatstructurethroughstrandinvasionof3′-overhangtoavoidtelomereerosion(Griffithetal.
,1999;Stanseletal.
,2001;Wangetal.
,2004).
POT1regulatestelom-eraseaccesstotelomereswithTPP1(LoayzaandDeLange,2003;Wangetal.
,2007;Nandakumaretal.
,2012).
TRF1isalsoinvolvedinthetelomericrepeat-containingRNAtranscrip-tion(TERRA)andrecentresultshaveshownthatTRF1aswellasTRF2arecrucialfortelomeremaintenanceduringreplica-tivestress(SchoeftnerandBlasco,2008;Martinezetal.
,2009;Munozetal.
,2009).
Knockoutshelterincomponentsinmouseembryonicbroblast(MEF)orinhibitionoftheexpressionoftheseproteinsoroverexpressionofdominantnegativeallelesoftheseproteinsinvitroorinculturedhumancelllinesleadtothecollapseoftelomerestructures,includingsuddentelomereloss,t-looprecombinationandtelomerefusion(Karlsederetal.
,1999;Wangetal.
,2004).
Oneoftheessentialfunctionsofshelterinistocaptelom-TIN2Rap1TRF2TRF1POT1Tpp15'end3'-overhangApolloRECQMre11TopIIaXPF/ERCC1ku70/80RAD51DORCNSB1ShelterinTRF2associatedfactorsFigure3.
Structureoftelomeresandrepresentativetelomericassociatedfactors.
ThepotentialnovelbiomarkersoftelomerecomplexinagingandcancerHigherEducationPressandSpringer-VerlagBerlinHeidelberg2013August2013|Volume4|Issue8|577ProteinCell&REVIEWlogicalSNPinTRF2genewhichmightbeduetothefactthatTRF2mutationisembryoniclethality.
ThissuggeststhatTRF2mightplayacenterroleinshelterinandtheabsenceofTRF2mightcauseamorevulnerabletissuedevelopmentorregen-erationfailurecomparedtoothershelterincomponents.
Alltheseindicatethatshelteriniscrucialfortelomerefunctionandtheabolishmentoftheseproteinsresultsingenomicinstabil-ityassevereastelomerelossduetocellpassageorduetotheabsenceoftelomeraseactivity.
Itmighthavemoreexac-erbatedconsequences,becauseitoccursmorebrutallythanprogressivetelomereloss.
TRF2,togetherwithothershelterincomponents,arepotentialbiomarkersforagingpathologies.
Althoughshelterincomponentsplayacomplimentaryroletotelomerasethroughcappingtelomerestructureandstabilizingtelomeres,higherdosageofshelterincomponentsactoppo-sitetoitsprotectivefunction.
OverexpressionofTRF2orTRF1inK5miceleadtotelomerelossandchromosomeaberration(Munozetal.
,2009),presagingsyndromeandtumorgenesis.
ThisisconcomitantwithclinicalreportsthatTRF2andTRF1levelsareabnormallyincreasedinpathologicalsamplesofgastriccancer,skincancer,lungcancer,etc.
(Munozetal.
,2005;Ningetal.
,2006;Hsuetal.
,2007).
Inaddition,telom-erasedeciencyinK5-TRF2miceacceleratesTRF2inducedcarcinogenesis,stronglysupportsthatTRF2overexpressioncouldspontaneouslygenerateafullytransformedtumorigenicphenotype,whereastelomeraseactivityisdispensibleduringmalignanttransformation(Blancoetal.
,2007).
Thus,TRF2overexpressionactsasapotentoncogenicevent.
Targetingshelterincomponents,especiallyTRF2mightbeanovelanti-cancerstrategy.
TelomereassociatedproteinsaretakingtheleadintelomereprotectionShelterinmembersperformtheirroleintelomereprotectionthroughinteractingwithalargenumberofassociatedproteins.
Theseshelterinaccessoryfactorsaremainlyinvolvedinnon-telomericfunctions,includingDNAdamagesignal(Mre11com-plex,911complex,etc.
),DNArepair(ku70/80,XPF/ERCC1,Apollo,RAD51D,etc.
)andDNAreplication(ORC,RecQ,TopIIa,etc.
).
Theyarerecruitedtoinducetheirfunctionattel-omeresbythespecialmodicationofshelterin(Fig.
3).
Recently,emergingevidencessuggestthatoneoftheseassociatedproteins,SNM1B/APOLLOinteractswithTRF2andplaysanimportantroleintelomereprotection(Lenainetal.
,2006;vanOverbeekanddeLange,2006;Yeetal.
,2010a).
SNM1B/APOLLOisa5′-exonucleasebelongingtothemetallo-β-lactamasefamily.
BesidesApollo,themetallo-β-lactamasefamily,whichhasacommondomainofβ-CPSF-Artemis-Snm1-Pso2,containsSNM1AandSNM1C/Artemis,andallofthemareinvolvedinDDRandrepairsystemviatheirnucleaseactivity.
SNM1Amediatesradiation-inducedDNArepair.
SN-M1C/ArtemislocalizesanddegradesthehairpinsgeneratedduringV(D)Jrecombination.
SNM1C/Artemisisalsoresponsi-blefortheNHEJrepairandIR-inducedDNAdamage.
SNM1B/APOLLOisinvolvedinICLrepair.
FivemainpaperspublishingatnearlythesametimetriedtoelucidatehowApolloprotectstelomeres,inadditiontoitsroleinICLrepair.
ApollodysfunctioninducedeitherbyRNAinterfer-enceorbyoverexpressionofnucleasedeadallelesleadstorobustincreaseinTIFandvarioustypesoftelomereaberra-tion,includingtelomerefreeends,chromatidfusionespeciallyleadinghandchromatidfusion,andfragiletelomeres.
Recentresultshaveshownthatthe5′-exonucleaseactivityofApollohasbeendemonstratedcrucialfortelomereprocessingduringreplication.
Itmightbeinvolvedintheprogressionofreplicationforktomaintaintheinnerpartoftelomeresthroughremovaloftheincorrectreplicativeproducts.
Thus,Apollomightbeimplicatedinthepreventionofforkcollapseorretrogressionattelomeres.
This5′-exonucleaseactivityisalsoshowntore-lievethepositivesupercoilstructureaheadofforkinducedbytopoisomeraseIIdepletion(Yeetal.
,2010a).
Besidesitsroleintelomerereplication,Apolloisalsocrucialfortelomerepro-cessingafterreplication.
Apolloknockoutinmouseembryonicbroblastcellsshows3′-overhanglossandtelomerefusioninleadingstrand,whichisregulatedbyTPP1,POT1andotherassociatedfactors(Lametal.
,2010;Wuetal.
,2010).
SeveralresultsshowthatApolloprotectstelomeresthroughrepressingATM,whereasothersdidn'telicitthedirectlinkthatApollomodulatesATMactivation.
Theseinconsistentresultsmightbeduetothevariantcellmodelstheyusedinexperi-mentassay,forexample,humancancercelllinesormouseembryoniccellsorduetotheinhibitingefficiencyofthenu-cleasesactivityofApollo(Demuthetal.
,2008;Lametal.
,2010;Wuetal.
,2012).
Thus,itisstillelusivewhetherApolloisresponsiblefortheinhibitionofATMorotherDDRpathwayinducedattelomeres.
ApolloisalsoinvolvedintheinhibitionofNHEJatuncappedtelomeres.
ApollodysfunctioninTRF2compromisedcellsresultsinexacerbationofchromosomeendfusioninducedbyNHEJ(Yeetal.
,2010a).
Thehighlevelsoftelomericend-to-endfusionsowingtoSnm1B/Apollomutationobservedinmouseembryonicbroblasts(MEFs)impairscellproliferationandresultsincellsenescenceorapoptosis(vanOverbeekanddeLange,2006;Lametal.
,2010).
Recently,theabovefunctionofSnm1B/Apollohasbeendemonstratedinvivoexperimentalstudyandclinicalreports.
Snm1B/Apollohomozygousnullmicedieatbirthwithdevel-opmentaldelayanddefectsinmultipleorgansystemsinp53independentpathway(Akhteretal.
,2010).
Moreover,aclinicalcasealsoshowsthatauniqueApollosplicevariantwasidenti-edinasevereHoyeraal-Hreidarsson(HH)syndromepatientwhoischaracterizedsevereprematureaging,bonemarrowfailure,andimmunodeciency(Touzotetal.
,2010),indicatingsuchatranscriptionalvariantofApollodoesresultinpatho-logicaltelomeredysfunction.
Moreover,amutatedDCLRE1BgeneofApolloidentiedwithabreakpointwithintheintron3ofDCLRE1BintheWilmstumors,anephroblastomathattypi-callyaffectschildren(Natrajanetal.
,2007).
Thesetwoclinicalstudiesattracttheattentionoftelomerediscoveries,andhigh-YimingLuetal.
578|August2013|Volume4|Issue8HigherEducationPressandSpringer-VerlagBerlinHeidelberg2013ProteinCell&REVIEWlightthatApolloisacrucialphysiologicalproteinintelomerephysiologyandtissuedevelopment.
ApollointeractswithTRF2andTPP1,maybeothershelterinmembersduringvariousstepsoftelomerereplicationtomaintaintelomereintegrationandprotectagainstDDRmachineryandDNArepairmachin-ery.
Overall,telomericcomplex,includingspecifictelomericsequencesanditsnucleoproteincappingstructureiscrucialelementresponsibleforlifespanbyeliminatingcancerandagingassociateddegenerativepathologies.
Thus,targetingtelomeresmightbeahopefulstrategyindependenttelomerasetocounteractawiderangeofdiseasesofvarianttissueoriginincludingcancer,stemcelldysfunctionandtissueregenerativeinability.
CONCLUSIONNobiomarkersexistthathasbeenassociatedwithsobroadspectrumofaffecteddiseasesandorgansastelomerecom-plex.
Telomerelengthisregardedasthemitoticalarmfortherenewalcapacityofstemcellandtissueregeneration.
Telom-eraseactivityisevenmoresensitivethanp53mutationasaclinicalbiomarkeroftumorinltration.
Also,targetingtelomerelengthandtelomerasecouldbeaneffectivepharmaceuti-calstrategytocureagingrelateddiseases,includingtissuedegenerationandcancer,regardlessoftissuespecicityandclinicalmanifestation.
Thus,managingtelomerelengthortheexpressionoftelomerasecontrolstheoriginofthesediseases.
Nowadays,pharmaceuticalmoleculestargetingtelomeraseforcancertherapyisongoingforclinicaltrialsandthestrategytoextendtelomerelengthbytelomerasereactivationhasbeenproveninthemousemodeltoimprovetissuefunctionandextendlifespan.
Thenextcrucialproblemistosolvewhetherexogenousexpressionoftelomeraseindysfunctionaltissueshouldbebalancedtoavoidmalignantproliferationbesidesitsmainfunctiontogainre-acquiredrenewalcapacity.
Fortunately,thecombinedoverexpressionoftelomeraseandtumorsup-pressiongeneinmousemodelhasbeendemonstratedasasolutionforlongevitywithoutincreasedonsetofoncogenesis.
Therefore,mediationoftelomeraseactivityisnotanextrava-ganthopetoreachthenaldestinationoflongevitywithhealthandlifequality(Fig.
4).
Moreimportantly,shelterinandtheirassociatedproteinshavedisplayedtheircomplimentroleinagingandcancertotelomerase,evidencedbyclinicalsamplesandmousemodels.
Moreover,theablationoftheseproteinsresultinmoredramat-icphenotypeintelomeredysfunctionandtissuedegeneration,whichexhibitmorerapidlythanthoseinducedbytelomerasedeciency.
Thisindicatesthattargetingtheseproteinsmightbemoresensitiveandeffectivethanoratleastthesameastargetingtelomerase,especiallyforthosewhoareantagonistictotelomeraseintervention.
Thus,itishighlyhypothesizedthatDiagnosis,predictionandsurveillanceTelomerelengthdetectionExpressionlevelofTRF2anditsassociatedfactorsTRAPassayfortelomeraseactivityAging/TissuefailureAdvancedcancerOverexpressionoftelomeraseandtumorsuppressorgene(Sp53/Sp16SARF/TgTERT)InhibitionoftelomeraseactivityBalanceofTRF2dosageanditsassociatedfactorsInvivomodelsClinicaltrialsTherapeuticstrategyFigure4.
Thepotentialclinicalvalueoftelomeresinlongevity.
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p53-andATM-dependentapoptosisinducedbytelomereslackingtheseproteinscouldbepotentialclinicalbiomarkersofagingorcancer,andthestudyontheseproteinsmightenableusben-etmorefromtelomerestodiscovernewdrugsforlongevity(Fig.
4).
TRF2andApolloarejusttwoexamples,fromwhichweknowthatshelterinandtheirassociatedproteinsarecrucialfortelomerefunction,aswellasagingandcancer.
Othershel-terinproteinsandtheirassociatedproteins,likeTIN2,TRF1orWRN,BLM,etc.
arealsoimplicatedinpresagingsyndromeandcancer,althoughthemolecularmechanismsmightbevari-ous.
Thus,furtherstudiesarenecessarytoidentifythefunc-tionoftheseproteinsintelomereprotection.
Althoughseveralclinicalstudieshavedemonstratedthattheexpressionleveloftheseproteinsareassociatedwithclinicalagingandcancer,furtherclinicalstudiesoflargescaleinvestigationinmulticenterareneededtoverifytheirexpressionlevelinpatients.
Itishopefulthatshelterinandtheirassociatedproteinswillprovokeaneweraoftelomereassociatedbiomedicalstudybydiscov-eringtelomericproteinbaseddiagnosticbiomarkerandthera-peuticstrategy.
ACKNOWLEDGEMENTSThisworkwassupportedbytheNationalNaturalScienceFoundationofChina(GrantNos.
81270433,81170491,and81000875),andtheFoundationforYoungScientistinShanghaiMunicipalHealthBureauinChina(GrantNo.
2010.
24).
ABBREVIATIONSDKC,dyskeratosiscongenital;HH,Hoyeraal-Hreidarsson;HR,ho-mologousrecombination;MEF,mouseembryonicfibroblast;NHEJ,non-homologousendingjoining;TIF,telomeredysfunctionfoci;TRAP,telomericrepeatamplicationprotocolCOMPLIANCEWITHETHICSGUIDELINESYimingLu,BohuaWei,TaoZhang,ZiChen,andJingYedeclarethattheyhavenoconictofinterest.
Thisarticledoesnotcontainanystudieswithhumanoranimalsub-jectsperformedbytheanyoftheauthors.
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