Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling IN...

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Autores: Prendergast, Lisa, McClurg, Urszula, Hristova, Rossitsa, Berlinguer-Palmini, Rolando, Greener, Sarah, Veicht, Katie, Hernandez, Inmaculada, Pasero, Philippe, Rico, Daniel, Higgins, Jonathan M. G., Gospodinov, Anastas, Papamichos-Chronakis, Manolis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/53395
Acceso en línea:http://hdl.handle.net/10230/53395
http://dx.doi.org/10.1038/s41467-020-18306-x
Access Level:acceso abierto
Palabra clave:Genètica
Càncer
Cèl·lules canceroses
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spelling Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viabilityPrendergast, LisaMcClurg, UrszulaHristova, RossitsaBerlinguer-Palmini, RolandoGreener, SarahVeicht, KatieHernandez, InmaculadaPasero, PhilippeRico, DanielHiggins, Jonathan M. G.Gospodinov, AnastasPapamichos-Chronakis, ManolisGenèticaCàncerCèl·lules cancerosesCollisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.Work in MPC lab is supported by Liverpool University, Newcastle University and a Wellcome Institutional Support Fund Award. Work done in A.G.’s lab was supported by Bulgarian National Science Fund grant # DN11/17. Work in the PP lab is supported by grants from the Agence Nationale pour la Recherche (ANR), the Ligue Contre le Cancer (équipe labellisée), SIRIC Montpellier Cancer (INCa Inserm DGOS 12553) and the MSDAvenir fund. ULM was funded by the Royal Society RG170342. IHL was funded from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 754510. Work in the DR lab is supported by a Wellcome Trust Seed Award in Science (206103/Z/17/Z). Work of JMGH was funded by a Wellcome Trust Investigator Award [106951/Z/15/Z] and a Royal Society Wolfson Research Merit AwardNature Research202220222020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/53395http://dx.doi.org/10.1038/s41467-020-18306-xreponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésinfo:eu-repo/grantAgreement/EC/H2020/754510© Lisa Prendergast et al. 2020. 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 madehttps://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/533952026-06-12T07:21:37Z
dc.title.none.fl_str_mv Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
title Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
spellingShingle Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
Prendergast, Lisa
Genètica
Càncer
Cèl·lules canceroses
title_short Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
title_full Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
title_fullStr Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
title_full_unstemmed Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
title_sort Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
dc.creator.none.fl_str_mv Prendergast, Lisa
McClurg, Urszula
Hristova, Rossitsa
Berlinguer-Palmini, Rolando
Greener, Sarah
Veicht, Katie
Hernandez, Inmaculada
Pasero, Philippe
Rico, Daniel
Higgins, Jonathan M. G.
Gospodinov, Anastas
Papamichos-Chronakis, Manolis
author Prendergast, Lisa
author_facet Prendergast, Lisa
McClurg, Urszula
Hristova, Rossitsa
Berlinguer-Palmini, Rolando
Greener, Sarah
Veicht, Katie
Hernandez, Inmaculada
Pasero, Philippe
Rico, Daniel
Higgins, Jonathan M. G.
Gospodinov, Anastas
Papamichos-Chronakis, Manolis
author_role author
author2 McClurg, Urszula
Hristova, Rossitsa
Berlinguer-Palmini, Rolando
Greener, Sarah
Veicht, Katie
Hernandez, Inmaculada
Pasero, Philippe
Rico, Daniel
Higgins, Jonathan M. G.
Gospodinov, Anastas
Papamichos-Chronakis, Manolis
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Genètica
Càncer
Cèl·lules canceroses
topic Genètica
Càncer
Cèl·lules canceroses
description Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.
publishDate 2020
dc.date.none.fl_str_mv 2020
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/53395
http://dx.doi.org/10.1038/s41467-020-18306-x
url http://hdl.handle.net/10230/53395
http://dx.doi.org/10.1038/s41467-020-18306-x
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/H2020/754510
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812455

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