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C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption

Author

Listed:
  • Abhishek Bharadwaj Sharma

    (University of Oxford)

  • Muhammad Khairul Ramlee

    (University of Oxford)

  • Joel Kosmin

    (University of Oxford)

  • Martin R. Higgs

    (University of Birmingham)

  • Amy Wolstenholme

    (University of Oxford)

  • George E. Ronson

    (University of Oxford
    University of Birmingham)

  • Dylan Jones

    (University of Oxford)

  • Daniel Ebner

    (University of Oxford)

  • Noor Shamkhi

    (University of Oxford)

  • David Sims

    (University of Oxford, John Radcliffe Hospital)

  • Paul W. G. Wijnhoven

    (Early Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus)

  • Josep V. Forment

    (Early Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus)

  • Ian Gibbs-Seymour

    (University of Oxford)

  • Nicholas D. Lakin

    (University of Oxford)

Abstract

While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors.

Suggested Citation

  • Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40779-9
    DOI: 10.1038/s41467-023-40779-9
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