HELZ is a RNA-DNA helicase that resolves R loops to facilitate homologous recombination repair
Abstract
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.
Article Details
Authors (31)
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
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University
Xiaofeng Yang
Zachary S. Buchwald
Xingming Deng
Kyle M. Miller
Bing Yao
Li Lan
Department of Molecular Genetics and Microbiology, Duke University
Weixing Zhao
David S. Yu