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<p>Senataxin (SETX), an RNA–DNA helicase, accumulates at transcription pause sites through the tumor suppressor BRCA1. Here, we provide mechanistic insight into how SETX–BRCA1 resolves transcription-associated R-loops to prevent deleterious outcomes. Specifically, we show that full-length SETX unwinds R-loops with broad specificity and that the complex of BRCA1 and its obligatory partner BARD1 binds R-loops and stimulates R-loop unwinding by SETX. BRCA1–BARD1 alleviates the inhibitory effect of RAD52 on SETX-mediated R-loop unwinding. We also demonstrate that phosphorylation of Ser642 in SETX promotes its interaction with BRCA1 through the tandem BRCT domain of the latter. Accordingly, mutations impacting the catalytic domain or Ser642 in SETX lead to R-loop accumulation, transcription–replication conflicts, replication fork stalling and DNA double-strand breaks in human cells. Thus, our results delineate the molecular basis for functional synergy between SETX and BRCA1–BARD1 in R-loop resolution and the mitigation of transcription–replication conflicts to preserve genome integrity.</p>

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Resolution of R-loops and transcription–replication conflicts by SETX–BRCA1–BARD1 complex

  • 期刊论文

  • 发表日期：

    2026年3月31日

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  • Arijit Dutta,
  • Jae-Hoon Ji,
  • Shahrez Syed,
  • Qingming Fang,
  • Pramiti Mukhopadhyay,
  • Hanzhou Wang,
  • Eva Loranc,
  • Daisy Medina,
  • Shahad Abdulsahib,
  • Shuo Zhou,
  • Miriam Tovar,
  • Jeff Wang,
  • Jane M. Benoit,
  • Fengshan Liang,
  • Nozomi Tomimatsu,
  • Julius O. Nyalwidhe,
  • Eloise Dray,
  • Amy Verway-Cohen,
  • Drew T. McDonald,
  • Bárbara de la Peña Avalos,
  • Wenjing Li,
  • Ane Olazabal Herrero,
  • O’Taveon Fitzgerald,
  • Alexander B. Taylor,
  • Youngho Kwon,
  • Oliver J. Semmes,
  • Miaw-Sheue Tsai,
  • Manjeet Rao,
  • Robert Hromas,
  • Sandeep Burma,
  • Yidong Chen,
  • Alexander V. Mazin,
  • Elizabeth Wasmuth,
  • Shaun K. Olsen,
  • Daohong Zhou,
  • Alexander J. R. Bishop,
  • Weixing Zhao,
  • Gary M. Kupfer,
  • Patrick Sung

摘要

Senataxin (SETX), an RNA–DNA helicase, accumulates at transcription pause sites through the tumor suppressor BRCA1. Here, we provide mechanistic insight into how SETX–BRCA1 resolves transcription-associated R-loops to prevent deleterious outcomes. Specifically, we show that full-length SETX unwinds R-loops with broad specificity and that the complex of BRCA1 and its obligatory partner BARD1 binds R-loops and stimulates R-loop unwinding by SETX. BRCA1–BARD1 alleviates the inhibitory effect of RAD52 on SETX-mediated R-loop unwinding. We also demonstrate that phosphorylation of Ser642 in SETX promotes its interaction with BRCA1 through the tandem BRCT domain of the latter. Accordingly, mutations impacting the catalytic domain or Ser642 in SETX lead to R-loop accumulation, transcription–replication conflicts, replication fork stalling and DNA double-strand breaks in human cells. Thus, our results delineate the molecular basis for functional synergy between SETX and BRCA1–BARD1 in R-loop resolution and the mitigation of transcription–replication conflicts to preserve genome integrity.