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

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.

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Publication Details

Journal
Nature Communications
Published
2026-07-23
DOI
https://doi.org/10.1038/s41467-026-75089-3
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Yingzi Hou, Erin C. Connolly, Anna Marie Kenney, Zachary S. Buchwald et al.
Nature Communications
DNA Repair Mechanisms
article

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

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

Abstract

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.

Nature CommunicationsVol. 17(1)
Emory University (US), The University of Texas at San Antonio Health Science Center (US), Duke University (US), Winship Cancer Institute
National Institutes of Health, Winship Cancer Institute, National Cancer Institute
Openalex Percentile: Top 15%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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