SUMO-1 modification of FEN1 facilitates its interaction with Rad9-Radl-Husl to counteract DNA replication stress
SUMO-1 modification of FEN1 facilitates its interaction with Rad9-Radl-Husl to counteract DNA replication stress作者机构：Institute of Nuclear-Agricultural Sciences Zhejiang University Hangzhou 310029 China Department of Cancer Genetics and Epigenetics City of Hope National Medical Center and Beckman Research Institute Duarte CA 91010 USA Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences Nanjing Normal University Nanjing 210046 China Department of Molecular Medicine City of Hope National Medical Center and Beckman Research Institute Duarte CA 91010 USA
出 版 物：《Journal of Molecular Cell Biology》 (分子细胞生物学报（英文版）)
年 卷 期：2018年第10卷第5期
页 面：460-474页
核心收录：
学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 1001[医学-基础医学(可授医学、理学学位)] 07[理学] 080704[工学-流体机械及工程] 08[工学] 0817[工学-化学工程与技术] 0807[工学-动力工程及工程热物理]
基 金：This work was supported by grants from the National Basic Research Program of China (2015CB910600) the National Natural Science Foundation of China (31700688) the National Key Research and Development Program of China (2017YFA0503900) and the Natural Science Foundation of Zhejiang Province (LY16C050003) to Y.I.H. and H.X. A part of the work presented in the current article was supported by the National Institutes of Health grants ROICA073764 to B.H.S and R50CA211397 to L.Z
主 题：flap endonuclease 1 Rad9-Rad1-Hus1 complex replication stress SUMOylation
摘 要：Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.
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