FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , |
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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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 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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