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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 principales: Prendergast, Lisa, McClurg, Urszula L., Hristova, Rossitsa, Berlinguer-Palmini, Rolando, Greener, Sarah, Veitch, Katie, Hernandez, Inmaculada, Pasero, Philippe, Rico, Daniel, Higgins, Jonathan M. G., Gospodinov, Anastas, Papamichos-Chronakis, Manolis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484789/
https://www.ncbi.nlm.nih.gov/pubmed/32913330
http://dx.doi.org/10.1038/s41467-020-18306-x
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author Prendergast, Lisa
McClurg, Urszula L.
Hristova, Rossitsa
Berlinguer-Palmini, Rolando
Greener, Sarah
Veitch, Katie
Hernandez, Inmaculada
Pasero, Philippe
Rico, Daniel
Higgins, Jonathan M. G.
Gospodinov, Anastas
Papamichos-Chronakis, Manolis
author_facet Prendergast, Lisa
McClurg, Urszula L.
Hristova, Rossitsa
Berlinguer-Palmini, Rolando
Greener, Sarah
Veitch, Katie
Hernandez, Inmaculada
Pasero, Philippe
Rico, Daniel
Higgins, Jonathan M. G.
Gospodinov, Anastas
Papamichos-Chronakis, Manolis
author_sort Prendergast, Lisa
collection PubMed
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.
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spelling pubmed-74847892020-09-21 Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability Prendergast, Lisa McClurg, Urszula L. Hristova, Rossitsa Berlinguer-Palmini, Rolando Greener, Sarah Veitch, Katie Hernandez, Inmaculada Pasero, Philippe Rico, Daniel Higgins, Jonathan M. G. Gospodinov, Anastas Papamichos-Chronakis, Manolis Nat Commun Article 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. Nature Publishing Group UK 2020-09-10 /pmc/articles/PMC7484789/ /pubmed/32913330 http://dx.doi.org/10.1038/s41467-020-18306-x Text en © The Author(s) 2020 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/.
spellingShingle Article
Prendergast, Lisa
McClurg, Urszula L.
Hristova, Rossitsa
Berlinguer-Palmini, Rolando
Greener, Sarah
Veitch, 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
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484789/
https://www.ncbi.nlm.nih.gov/pubmed/32913330
http://dx.doi.org/10.1038/s41467-020-18306-x
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