HELZ promotes R loop resolution to facilitate DNA double-strand break repair by homologous recombination

Haji-Seyed-Javadi, R.; Koyen, A. E.; Rath, S. K.; Madden, M. Z.; Hou, Y.; Song, B. S.; Kenney, A. M.; Lan, L.; Yao, B.; Yu, D. S.

doi:10.1101/2023.12.14.571747

bioRxiv · 10.1101/2023.12.14.571747

HELZ promotes R loop resolution to facilitate DNA double-strand break repair by homologous recombination

Haji-Seyed-Javadi, R.·Koyen, A. E.·Rath, S. K.·Madden, M. Z.·Hou, Y.·Song, B. S.·Kenney, A. M.·Lan, L.·Yao, B.·Yu, D. S.

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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 5ssRNA 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. Our findings define a role for HELZ in resolving R loops critical for HR that promotes genome stability and governs DSB-inducing agent resistance.

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Haji-Seyed-Javadi, R., Koyen, A. E., Rath, S. K., Madden, M. Z., Hou, Y., Song, B. S., Kenney, A. M., Lan, L., Yao, B., Yu, D. S.. 2023-12-15. HELZ promotes R loop resolution to facilitate DNA double-strand break repair by homologous recombination. https://doi.org/10.1101/2023.12.14.571747

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