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

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dc.contributor.authorSilva, Bruno
dc.contributor.authorPentz, Richard
dc.contributor.authorFigueira, Ana Margarida
dc.contributor.authorArora, Rajika
dc.contributor.authorLee, Yong Woo
dc.contributor.authorHodson, Charlotte
dc.contributor.authorWischnewski, Harry
dc.contributor.authorDeans, Andrew J.
dc.contributor.authorAzzalin, Claus Maria
dc.date.accessioned2021-03-25T13:37:30Z
dc.date.available2021-03-25T13:37:30Z
dc.date.issued2019
dc.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/.pt_PT
dc.description.abstractTelomerase 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.pt_PT
dc.description.sponsorshipResearch 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2019 May 28;10(1):2253pt_PT
dc.identifier.doi10.1038/s41467-019-10179-zpt_PT
dc.identifier.eissn2041-1723
dc.identifier.urihttp://hdl.handle.net/10451/47062
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationIF/01269/2015pt_PT
dc.relationTelomeric R-loop-mediated recombination in the alternative lengthening of telomeres pathway: towards designing novel therapeutic avenues for cancer therapy
dc.relationInstituto de Medicina Molecular
dc.relation.publisherversionhttps://www.nature.com/ncomms/pt_PT
dc.titleFANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loopspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberPTDC/MED-ONC/28282/2017
oaire.awardNumberPTDC/BIA-MOL/29352/2017
oaire.awardNumberUID/BIM/50005/2019
oaire.awardTitleTelomeric R-loop-mediated recombination in the alternative lengthening of telomeres pathway: towards designing novel therapeutic avenues for cancer therapy
oaire.awardTitleInstituto de Medicina Molecular
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F28282%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FBIA-MOL%2F29352%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F50005%2F2019/PT
oaire.citation.issue1pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
person.familyNameSousa Silva
person.familyNamePentz
person.familyNameArora
person.familyNameAzzalin
person.givenNameBruno Adriano
person.givenNameRichard
person.givenNameRajika
person.givenNameClaus Maria
person.identifier.ciencia-id6E10-32B5-C862
person.identifier.orcid0000-0002-1452-9779
person.identifier.orcid0000-0003-2034-8760
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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