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

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    Authors
    Prendergast, Lisa
    McClurg, U. L.
    Hristova, R.
    Berlinguer-Palmini, R.
    Greener, S.
    Veitch, K.
    Hernandez, I.
    Pasero, P.
    Rico, D.
    Higgins, J. M. G.
    Gospodinov, A.
    Papamichos-Chronakis, M.
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    Affiliation
    Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne, NE2 4HH, UK.
    Issue Date
    2020
    
    Metadata
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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.
    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.
    Journal
    Nature Communications
    URI
    http://hdl.handle.net/10541/623338
    DOI
    10.1038/s41467-020-18306-x
    PubMed ID
    32913330
    Additional Links
    https://dx.doi.org/10.1038/s41467-020-18306-x
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-020-18306-x
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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