rev bras hematol hemoter. 2017;39(2):98–99
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Scientific
Comment
Stressed
ends:
telomere
attrition
in
chronic
diseases
夽
Wilson
Chun
Fok,
Luis
Francisco
Zirnberger
Batista
∗WashingtonUniversityinSt.Louis,St.Louis,UnitedStates
TelomeresareDNA–proteinstructuresthatcapchromosomal endsandprotectthemfromdegradation.Invertebrates,these sequencesarecomposedoflongstretchesofTTAGGGrepeats thatcanextend forup to15 kilobases(kb)inhumans and 100kbinrodents.ThetelomericDNAiscomposedofalong double-strandedtract thatends inashort, single-stranded overhang.TelomericDNAisboundbyshelterin,alarge multi-subunitproteincomplexthatpreventsthechromosomeends from being recognized as aDNA break,and inhibits inap-propriate recombination. Inhibition or deletion of specific shelterincomponentsresultsinalocalDNAdamageresponse atchromosomeends,leadingtorobustactivationofDNA dam-age pathways and cell death. Due to the inability ofDNA polymerasestofullyreplicatechromosomeendsatthelagging strand,ateverycelldivisionthereisalossofupto200base pairsoftelomericDNA.1 Itissuggestedthatcriticallyshort telomeres carry insufficientshelterin components to avoid ataxiatelangiectasiamutated(ATM)andataxia telangiecta-siaand‘rad3-related’(ATR)signalingcascades.2Accordingly, cells with short telomeres present classical DNA damage-responses,suchasformationoftelomereinducedfoci(TIFs), stabilizationofp53,and activationofp21.2 Thetelomerase ribonucleoprotein,whichisabletosynthesizetelomeresfrom anRNA template, provides acompensatory mechanism to continuoustelomereshortening.3Inhumanshowever, telom-eraseisonlyactiveinstemandprogenitorcells,andisnot abletomaintaintelomerelengththroughoutlifespan.4Inthis regard,telomereshorteningcanbeseenasamolecularclock forcellularaging.
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2017.02.007.
夽
SeepaperbyColellaetal.inRevBrasHematolHemoter.2017;39(2):140–5.
∗ Correspondingauthorat:DepartmentofMedicine,WashingtonUniversityinSt.Louis,660SEuclidAve,St.Louis,MO63110,USA.
E-mailaddress:lbatista@wustl.edu(L.F.Batista).
The detrimental effects of telomere shortening can be seeninpatientssufferingfrom“telomeropathies”,agroupof clinicallydiversediseaseswherepatientshavemutationsin different genesnecessaryfortelomere maintenance.5 With thepopularizationofDNAsequencingtechnologiesfor clin-ical diagnostics,the number ofdiseases directly relatedto mutationsintelomerebiologygeneshasincreased,alongwith thenumberofdifferentgenesmutatedinthesepatients,and withthenumberofdifferentmutationsfoundineachgene. Thesediseases,whichrangefromseverepediatric complica-tions(suchasbonemarrowfailureindyskeratosiscongenita and Hoyeraal–Hreidarsson syndromes) to adult-onset dis-eases(suchasliverfibrosisandcirrhosis,aswellaspulmonary fibrosis) share the same molecular determinant: telomeres thatareat,orbelow,thefirstpercentileinlengthwhen com-paredtoage-matchedcontrols.Interestingly,telomerelength isaregulatorofdiseaseseverityinpatientsharboring muta-tionsintelomerebiologygenes,withmoreseveremutations causing moresevere phenotypes atyounger ages. In addi-tion,infamilieswithautosomal-dominantmutations,disease phenotypes are observed progressively earlier in age from onegenerationtothenext,aprocessdescribedastelomeric geneticanticipation.
Interestingly,inrecentyears,telomere attritionhasalso beendescribedinanumberofdifferentconditions,ranging fromdepressiontopoorimmunefunctionanddiabetes,where patientsdonothavemutationsintelomerasebiologygenes.6 Mostnotably,shorterleukocytetelomerelength(LTL)hasbeen directly associated withcardiovascular disease7 and it has
http://dx.doi.org/10.1016/j.bjhh.2017.03.004
rev bras hematol hemoter. 2017;39(2):98–99
99
beenproposedthatLTLcanbearelevantbiomarkerof car-diovascularaging.8Theprevalenttheoryisthatinflammation and oxidativestress trigger afasterimmune cell turnover, whichinturnleadstoashorterLTL.9Thisisinlinewiththe datashownbyColellaetal.,inthisissueoftheBrazilianJournal ofHematologyandHemotherapy.10Intheirwork,theauthors analyzedtelomerelengthsfromperipheralbloodleukocytesof sicklecelldisease(SCD)patients.Theauthorsdemonstrated bydifferentmethodsthattelomeresaresignificantlyshorter inSCDpatients incomparisontoage-matchedcontrols.In addition,withinthecohortofSCDpatients,telomere shorten-ingcorrelatedwithdiseaseseverity,withhomozygousmutant patientshavingsignificantlyshortertelomeresthan heterozy-gous patients. Moreover,patientson hydroxyurea alsohad significantlyshorter telomeres whencompared topatients nottreatedwiththedrug.Interestingly,inSCDpatients, telo-merelengthdidnotcorrelatewithage,whichindicatesthat inthesepatientsthetelomereattritioncausedbythedisease phenotypeissignificantenoughtoablatethemild,gradual shorteningoftelomeresthatoccurswithnaturaltissueaging. Combined, the results presented by Colella et al., indi-catethatinSCD,inflammationandoxidativestress(elevated oxidativestress burden isa well-establishedoccurrence in SCD)alsocontributetotelomereattrition.10Whilefuture stud-iesshouldcontinuetodecipher theroleoftelomere length andhumandisease,andestablishiftelomereattritionplaysa directroleindiseaseprogression,thedatashowedbyColella etal.inthisissuehelpcementtheimportanceoftelomere biologyasamarkerofcellularandorganismalhealth.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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