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SUMO-1 modification of FEN1 facilitates its interaction with Rad9–Rad1–Hus1 to counteract DNA replication stress
Xiaoli Xu 1,† , Rongyi Shi 1,† , Li Zheng 2,† , Zhigang Guo 3,† , Liangyan Wang 1 , Mian Zhou 2 , Ye Zhao 1 , Bing Tian 1 , Khue Truong 4 , Yuan Chen 4 , Binghui Shen 2,* , Yuejin Hua 1,* , and Hong Xu 1,*
1 Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029, China
2 Department of Cancer Genetics and Epigenetics, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA
3 Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing 210046, China
4 Department of Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA
Authors contributed equally to this work.
*Correspondence to:Binghui Shen, E-mail: bshen@coh.org; Yuejin Hua, E-mail: yjhua@zju.edu.cn; Hong Xu, E-mail: 0011104@zju.edu.cn
J Mol Cell Biol, Volume 10, Issue 5, October 2018, Pages 460-474  https://doi.org/10.1093/jmcb/mjy047
Keyword: flap endonuclease 1, Rad9–Rad1–Hus1 complex, replication stress, SUMOylation
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 Rad9–Rad1–Hus1 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-stalling agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Rad9–Rad1–Hus1 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-stalling agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.