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

Author

Listed:
  • Lisa Prendergast

    (Newcastle University
    The University of Manchester)

  • 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
    The Barcelona Institute of Science and Technology)

  • 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
    Newcastle University)

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.

Suggested Citation

  • Lisa Prendergast & Urszula L. McClurg & Rossitsa Hristova & Rolando Berlinguer-Palmini & Sarah Greener & Katie Veitch & Inmaculada Hernandez & Philippe Pasero & Daniel Rico & Jonathan M. G. Higgins & , 2020. "Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18306-x
    DOI: 10.1038/s41467-020-18306-x
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    Cited by:

    1. Aleix Bayona-Feliu & Emilia Herrera-Moyano & Nibal Badra-Fajardo & Iván Galván-Femenía & María Eugenia Soler-Oliva & Andrés Aguilera, 2023. "The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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