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

Lisa Prendergast, Urszula L. McClurg, Rossitsa Hristova, Rolando Berlinguer-Palmini, Sarah Greener, Katie Veitch, Inmaculada Hernandez, Philippe Pasero, Daniel Rico, Jonathan M. G. Higgins, Anastas Gospodinov () and Manolis Papamichos-Chronakis ()
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Lisa Prendergast: Newcastle University
Urszula L. McClurg: University of Liverpool
Rossitsa Hristova: Bulgarian Academy of Sciences
Rolando Berlinguer-Palmini: Newcastle University
Sarah Greener: Newcastle University
Katie Veitch: Newcastle University
Inmaculada Hernandez: Newcastle University
Philippe Pasero: CNRS UMR9002 and University of Montpellier, Equipe Labéllisée Ligue Contre le Cancer
Daniel Rico: Newcastle University
Jonathan M. G. Higgins: Newcastle University
Anastas Gospodinov: Bulgarian Academy of Sciences
Manolis Papamichos-Chronakis: University of Liverpool

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18306-x

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