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

Prendergast, Lisa, McClurg, Urszula L ORCID: 0000-0003-2631-4174, Hristova, Rossitsa, Berlinguer-Palmini, Rolando, Greener, Sarah, Veitch, Katie, Hernandez, Inmaculada, Pasero, Philippe, Rico, Daniel, Higgins, Jonathan MG
et al (show 2 more authors) (2020) Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability. Nature Communications, 11 (1). 4534-.

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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 <jats:italic>cis</jats:italic>. 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.

Item Type: Article
Uncontrolled Keywords: cell biology, chromatin remodelling, molecular biology, stalled forks
Depositing User: Symplectic Admin
Date Deposited: 11 Sep 2020 07:26
Last Modified: 18 Jan 2023 23:33
DOI: 10.1038/s41467-020-18306-x
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