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

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.

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Publication Details

Journal
Nature Communications
Published
2026-07-23
DOI
https://doi.org/10.1038/s41467-026-75088-4
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Youngho Kwon, Siyuan Zheng, Tengyang Ni, Tram Thi Ngoc Nguyen et al.
Nature Communications
DNA Repair Mechanisms
article

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

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

Abstract

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.

Nature CommunicationsVol. 17(1)
NC Department of Health and Human Services (US), North Carolina Department of Environmental Quality (US), Texas State University (US), North Carolina State University (US), Emory University (US), The University of Texas at San Antonio Health Science Center (US), Duke University (US)
National Science Foundation, American Cancer Society, Cancer Prevention and Research Institute of Texas, Max and Minnie Tomerlin Voelcker Fund, North Carolina State University, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences
Good health and well-being
Openalex Percentile: Top 15%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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