FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops

Detalhes bibliográficos
Autor(a) principal: Silva, Bruno
Data de Publicação: 2019
Outros Autores: Pentz, Richard, Figueira, Ana Margarida, Arora, Rajika, Lee, Yong Woo, Hodson, Charlotte, Wischnewski, Harry, Deans, Andrew J., 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/10451/47062
Resumo: © The Author(s) 2019. 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 FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops© The Author(s) 2019. 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/.Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.Research in the Azzalin laboratory was supported by the Swiss National Science Foundation (31003A_160338), the European Molecular Biology Organization (IG3576) and the Fundação para a Ciência e a Tecnologia (IF/01269/2015; PTDC/MED-ONC/28282/2017; PTDC/BIA-MOL/29352/2017). R.P. was supported by a Swiss National Science Foundation Doc.Mobility fellowship (P1EZP3-168771). Research in the Deans laboratory was supported by the Cancer Council of Victoria, Australian National Health and Medical Research Council (APP1139099), Buxton trust and the Victorian Government’s OIS Program. A.J.D is a Victorian Cancer Agency fellow. Publication costs were supported by UID/BIM/50005/2019, project funded by the Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.Springer NatureRepositório da Universidade de LisboaSilva, BrunoPentz, RichardFigueira, Ana MargaridaArora, RajikaLee, Yong WooHodson, CharlotteWischnewski, HarryDeans, Andrew J.Azzalin, Claus Maria2021-03-25T13:37:30Z20192019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/47062engNat Commun. 2019 May 28;10(1):225310.1038/s41467-019-10179-z2041-1723info: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:RCAAP2023-11-08T16:49:42Zoai:repositorio.ul.pt:10451/47062Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:08.979717Repositório 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 FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
title FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
spellingShingle FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
Silva, Bruno
title_short FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
title_full FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
title_fullStr FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
title_full_unstemmed FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
title_sort FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
author Silva, Bruno
author_facet Silva, Bruno
Pentz, Richard
Figueira, Ana Margarida
Arora, Rajika
Lee, Yong Woo
Hodson, Charlotte
Wischnewski, Harry
Deans, Andrew J.
Azzalin, Claus Maria
author_role author
author2 Pentz, Richard
Figueira, Ana Margarida
Arora, Rajika
Lee, Yong Woo
Hodson, Charlotte
Wischnewski, Harry
Deans, Andrew J.
Azzalin, Claus Maria
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Silva, Bruno
Pentz, Richard
Figueira, Ana Margarida
Arora, Rajika
Lee, Yong Woo
Hodson, Charlotte
Wischnewski, Harry
Deans, Andrew J.
Azzalin, Claus Maria
description © The Author(s) 2019. 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 2019
dc.date.none.fl_str_mv 2019
2019-01-01T00:00:00Z
2021-03-25T13:37:30Z
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/10451/47062
url http://hdl.handle.net/10451/47062
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Nat Commun. 2019 May 28;10(1):2253
10.1038/s41467-019-10179-z
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 Springer Nature
publisher.none.fl_str_mv Springer Nature
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
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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