Human HELQ regulates DNA end resection at DNA double-strand breaks and stalled replication forks

Author:

Zhao Yuqin1,Hou Kaiping1,Li Youhang1,Hao Shuailin1,Liu Yu1,Na Yinan1,Li Chao1,Cui Jian1,Xu Xingzhi2ORCID,Wu Xiaohua3ORCID,Wang Hailong1ORCID

Affiliation:

1. Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University , Beijing  100048 , China

2. Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering, China Shenzhen University School of Medicine , Shenzhen , Guangdong  518060 , China

3. Department of Molecular Medicine, The Scripps Research Institute , La Jolla , CA  92037 , USA

Abstract

Abstract Following a DNA double strand break (DSB), several nucleases and helicases coordinate to generate single-stranded DNA (ssDNA) with 3′ free ends, facilitating precise DNA repair by homologous recombination (HR). The same nucleases can act on stalled replication forks, promoting nascent DNA degradation and fork instability. Interestingly, some HR factors, such as CtIP and BRCA1, have opposite regulatory effects on the two processes, promoting end resection at DSB but inhibiting the degradation of nascent DNA on stalled forks. However, the reason why nuclease actions are regulated by different mechanisms in two DNA metabolism is poorly understood. We show that human HELQ acts as a DNA end resection regulator, with opposing activities on DNA end resection at DSBs and on stalled forks as seen for other regulators. Mechanistically, HELQ helicase activity is required for EXO1-mediated DSB end resection, while ssDNA-binding capacity of HELQ is required for its recruitment to stalled forks, facilitating fork protection and preventing chromosome aberrations caused by replication stress. Here, HELQ synergizes with CtIP but not BRCA1 or BRCA2 to protect stalled forks. These findings reveal an unanticipated role of HELQ in regulating DNA end resection at DSB and stalled forks, which is important for maintaining genome stability.

Funder

National Natural Science Foundation of China

Beijing Natural Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference96 articles.

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1. Helicase HELQ: Molecular Characters Fit for DSB Repair Function;International Journal of Molecular Sciences;2024-08-08

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