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

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. Wijnhoven, Josep V. Forment, Ian Gibbs-Seymour and Nicholas D. Lakin ()
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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
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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40779-9

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