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Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
Prendergast, Lisa McClurg, U. L. Hristova, R. Berlinguer-Palmini, R. Greener, S. Veitch, K. Hernandez, I. Pasero, P. Rico, D. Higgins, J. M. G.
Prendergast, Lisa
McClurg, U. L.
Hristova, R.
Berlinguer-Palmini, R.
Greener, S.
Veitch, K.
Hernandez, I.
Pasero, P.
Rico, D.
Higgins, J. M. G.
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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.
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Date
2020
Publisher
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From UNPAYWALL
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Article
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;11(1):4534.