TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells

Detalhes bibliográficos
Autor(a) principal: Silva, Bruno
Data de Publicação: 2021
Outros Autores: Arora, Rajika, Bione, Silvia, Azzalin, Claus Maria
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/48677
Resumo: © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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spelling TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.This work was supported by the European Molecular Biology Organization (IG3576), the Fundação para a Ciência e a Tecnologia (IF/01269/2015; PTDC/MED-ONC/28282/2017; PTDC/BIA-MOL/29352/2017) and the European Union’s Horizon 2020 Research and Innovation Programme (GA No. 857119 – RiboMed).https://www.nature.com/ncomms/Repositório da Universidade de LisboaSilva, BrunoArora, RajikaBione, SilviaAzzalin, Claus Maria2021-06-21T16:17:00Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/48677engNat Commun 12, 3760 (2021)10.1038/s41467-021-24097-62041-1723info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:52:01Zoai:repositorio.ul.pt:10451/48677Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:00:26.190840Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
title TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
spellingShingle TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
Silva, Bruno
title_short TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
title_full TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
title_fullStr TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
title_full_unstemmed TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
title_sort TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
author Silva, Bruno
author_facet Silva, Bruno
Arora, Rajika
Bione, Silvia
Azzalin, Claus Maria
author_role author
author2 Arora, Rajika
Bione, Silvia
Azzalin, Claus Maria
author2_role author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Silva, Bruno
Arora, Rajika
Bione, Silvia
Azzalin, Claus Maria
description © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
publishDate 2021
dc.date.none.fl_str_mv 2021-06-21T16:17:00Z
2021
2021-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/48677
url http://hdl.handle.net/10451/48677
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Nat Commun 12, 3760 (2021)
10.1038/s41467-021-24097-6
2041-1723
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv https://www.nature.com/ncomms/
publisher.none.fl_str_mv https://www.nature.com/ncomms/
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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