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<p>R-loops are transcription-induced, three-stranded nucleic acid structures that, if not properly resolved, can disrupt DNA repair and compromise genome stability. BRCA2, a tumor suppressor vital for homologous recombination (HR), also contributes to R-loop regulation, though the underlying mechanisms remain poorly understood. Here, we identify HELZ as a direct BRCA2 interactor and characterize it as an ssRNA-specific R-loop resolvase. BRCA2 enhances HELZ helicase activity and promotes its recruitment to R-loops. Importantly, HELZ resolves R-loops at DNA double-strand breaks, enabling efficient DNA end resection and HR, particularly within transcriptionally active genomic regions. We further demonstrate that HELZ is critical for R-loop clearance in cancers with elevated transcriptional activity and R-loop accumulation, such as estrogen receptor-positive breast cancer, where it becomes essential for cell survival under estrogen-induced transcriptional stress. These findings establish HELZ as a BRCA2-dependent regulator of R-loop homeostasis and identify it as a potential biomarker and therapeutic target in R-loop-driven malignancies.</p>

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HELZ-BRCA2 complex resolves R-loops to drive transcription-coupled homologous recombination

  • 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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  • Wenjing Li,
  • Bo Wu,
  • Boya Gao,
  • Elizabeth M. Irvin,
  • Arijit Ghosh,
  • Lillian Eliaz,
  • Yuxin Huang,
  • Youngho Kwon,
  • Clara M. Stiefel,
  • Tram Thi Ngoc Nguyen,
  • David Zhao,
  • Humberto Javier Suarez,
  • Tengyang Ni,
  • Salvador Alejo,
  • O’Taveon Fitzgerald,
  • Xuemei Song,
  • Sandip Kumar Rath,
  • Elizabeth V. Wasmuth,
  • David S. Yu,
  • Siyuan Zheng,
  • Justin Leung,
  • Xiaoyu Xue,
  • Hong Wang,
  • Jae-Hoon Ji,
  • Li Lan,
  • Weixing Zhao

摘要

R-loops are transcription-induced, three-stranded nucleic acid structures that, if not properly resolved, can disrupt DNA repair and compromise genome stability. BRCA2, a tumor suppressor vital for homologous recombination (HR), also contributes to R-loop regulation, though the underlying mechanisms remain poorly understood. Here, we identify HELZ as a direct BRCA2 interactor and characterize it as an ssRNA-specific R-loop resolvase. BRCA2 enhances HELZ helicase activity and promotes its recruitment to R-loops. Importantly, HELZ resolves R-loops at DNA double-strand breaks, enabling efficient DNA end resection and HR, particularly within transcriptionally active genomic regions. We further demonstrate that HELZ is critical for R-loop clearance in cancers with elevated transcriptional activity and R-loop accumulation, such as estrogen receptor-positive breast cancer, where it becomes essential for cell survival under estrogen-induced transcriptional stress. These findings establish HELZ as a BRCA2-dependent regulator of R-loop homeostasis and identify it as a potential biomarker and therapeutic target in R-loop-driven malignancies.