HELZ is a RNA-DNA helicase that resolves R loops to facilitate homologous recombination repair
- 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
2026-07-23
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.