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

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

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

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dc.contributor.author Prendergast, Lisa
dc.contributor.author McClurg, Urszula
dc.contributor.author Hristova, Rossitsa
dc.contributor.author Berlinguer-Palmini, Rolando
dc.contributor.author Greener, Sarah
dc.contributor.author Veicht, Katie
dc.contributor.author Hernandez, Inmaculada
dc.contributor.author Pasero, Philippe
dc.contributor.author Rico, Daniel
dc.contributor.author Higgins, Jonathan M. G.
dc.contributor.author Gospodinov, Anastas
dc.contributor.author Papamichos-Chronakis, Manolis
dc.date.accessioned 2022-06-07T09:05:49Z
dc.date.available 2022-06-07T09:05:49Z
dc.date.issued 2020
dc.description.abstract 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.
dc.description.sponsorship 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 Award
dc.format.mimetype application/pdf
dc.identifier.citation Prendergast L, McClurg UL, Hristova R, Berlinguer-Palmini R, Greener S, Veitch K et al. Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability. Nat Commun. 2020 Sep 10;11(1):4534. DOI:10.1038/s41467-020-18306-x
dc.identifier.doi http://dx.doi.org/10.1038/s41467-020-18306-x
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/53395
dc.language.iso eng
dc.publisher Nature Research
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/754510
dc.rights © 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 made
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject.other Genètica
dc.subject.other Càncer
dc.subject.other Cèl·lules canceroses
dc.title Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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