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The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted

2022Artigo científico Acesso aberto
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dc.contributor.authorSilva, Bruno
dc.contributor.authorArora, Rajika
dc.contributor.authorAzzalin, Claus Maria
dc.date.accessioned2022-09-21T14:41:26Z
dc.date.available2022-09-21T14:41:26Z
dc.date.issued2022
dc.descriptionCopyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).pt_PT
dc.description.abstractA substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.pt_PT
dc.description.sponsorshipThis work was supported by the Fundação para a Ciência e a Tecnologia (grants PTDC/BIA-MOL/6624/2020, PTDC/MED-ONC/7864/2020 to C.M.A. and B.S., and award 2021.00143.CEECIND to C.M.A.), European Molecular Biology Organization (grant IG3576 to C.M.A.), and LaCaixa Foundation (grant LCF/PR/HP21/52310016 to C.M.A.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationProc Natl Acad Sci USA. 2022 Sep 27;119(39):e2208669119pt_PT
dc.identifier.doi10.1073/pnas.2208669119pt_PT
dc.identifier.eissn1091-6490
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/10451/54541
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNational Academy of Sciencept_PT
dc.relationIG3576pt_PT
dc.relationAssembly and functions of the mammalian telomeric deoxyribo/ribonucleoprotein particle at chromosome ends and beyond
dc.relationNot Available
dc.relation.publisherversionhttps://www.pnas.org/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMus81pt_PT
dc.subjectTERRApt_PT
dc.subjectAlternative lengthening of telomerespt_PT
dc.subjectTelomere transcriptionpt_PT
dc.titleThe alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restrictedpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberPTDC/BIA-MOL/6624/2020
oaire.awardNumberPTDC/MED-ONC/7864/2020
oaire.awardNumberCEECIND/00143/2017/CP1459/CT0003
oaire.awardTitleAssembly and functions of the mammalian telomeric deoxyribo/ribonucleoprotein particle at chromosome ends and beyond
oaire.awardTitleNot Available
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-MOL%2F6624%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F7864%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F00143%2F2017%2FCP1459%2FCT0003/PT
oaire.citation.issue39pt_PT
oaire.citation.titleProceedings of the National Academy of Sciencespt_PT
oaire.citation.volume119pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamCEEC IND 2017
person.familyNameSousa Silva
person.familyNameArora
person.familyNameAzzalin
person.givenNameBruno Adriano
person.givenNameRajika
person.givenNameClaus Maria
person.identifier.ciencia-id6E10-32B5-C862
person.identifier.orcid0000-0002-1452-9779
person.identifier.orcid0000-0001-9396-3671
person.identifier.orcid0000-0002-9396-1980
person.identifier.ridK-3898-2015
person.identifier.scopus-author-id57209021272
person.identifier.scopus-author-id55116085500
person.identifier.scopus-author-id6602600026
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscoverya43f423d-cfc5-4a4e-b713-001912a4b833
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