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<p>R loop homeostasis is critical for DNA double-strand break (DSB) repair; however, how R loops are resolved in this context is poorly understood. Here, we define HELZ as a unique RNA-DNA helicase that resolves R loops to facilitate homologous recombination (HR) repair. From a synthetic lethal etoposide resistance siRNA screen, we found that HELZ depletion causes R loop-mediated hypersensitivity to DSB-inducing agents, and HELZ localizes and binds to DSBs. HELZ preferentially binds to and unwinds RNA-DNA hybrids with 5’ssRNA overhangs to promote R loop resolution genome-wide and at DSBs. Interestingly, HELZ facilitates BRCA1 recruitment to DSBs by preventing R loop accumulation, thereby promoting DNA end resection and HR to prevent R loop mediated genomic instability. In summary, we show that HELZ resolves R loops critical for HR, thereby promoting genome stability and resistance to DSB-inducing agents.</p>

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HELZ is a RNA-DNA helicase that resolves R loops to facilitate homologous recombination repair

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Ramona Haji-Seyed-Javadi,
  • Allyson E. Koyen,
  • Sandip K. Rath,
  • Bo Wu,
  • Matthew Z. Madden,
  • Yingzi Hou,
  • Priya Kapoor-Vazirani,
  • Roshika Roshika,
  • Meili Aiello,
  • Nho Cong Luong,
  • Wei-Che Tseng,
  • Fatmata Sesay,
  • John S. Kim,
  • Tony Tan,
  • Seohyun Kim,
  • Boya Gao,
  • Boying S. Song,
  • Anna M. Kenney,
  • Erin C. Connolly,
  • Lily Yang,
  • Blerta Xhemalce,
  • Xiaoxian Li,
  • Jeffrey M. Switchenko,
  • Xiaofeng Yang,
  • Zachary S. Buchwald,
  • Xingming Deng,
  • Kyle M. Miller,
  • Bing Yao,
  • Li Lan,
  • Weixing Zhao,
  • David S. Yu

摘要

R loop homeostasis is critical for DNA double-strand break (DSB) repair; however, how R loops are resolved in this context is poorly understood. Here, we define HELZ as a unique RNA-DNA helicase that resolves R loops to facilitate homologous recombination (HR) repair. From a synthetic lethal etoposide resistance siRNA screen, we found that HELZ depletion causes R loop-mediated hypersensitivity to DSB-inducing agents, and HELZ localizes and binds to DSBs. HELZ preferentially binds to and unwinds RNA-DNA hybrids with 5’ssRNA overhangs to promote R loop resolution genome-wide and at DSBs. Interestingly, HELZ facilitates BRCA1 recruitment to DSBs by preventing R loop accumulation, thereby promoting DNA end resection and HR to prevent R loop mediated genomic instability. In summary, we show that HELZ resolves R loops critical for HR, thereby promoting genome stability and resistance to DSB-inducing agents.