Human flap endonuclease 1 (FEN1) is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. Our previous study showed that 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 stalled DNA replication fork repair, and undergoes SUMOylation by SUMO-1. Here, we report that succinylation of FEN1 was stimulated in response to DNA replication fork-stalling agents, such as UV irradiation, hydroxyurea, camptothecin, and mitomycin C. K200 is a key succinylation site of FEN1 that is essential for gap endonuclease activity and could be suppressed by methylation and stimulated by phosphorylation to promote SUMO-1 modification. Succinylation at K200 of FEN1 promoted the interaction of FEN1 with the Rad9-Rad1-Hus1 complex to rescue stalled replication forks. Impairment of FEN1 succinylation led to the accumulation of DNA damage and heightened sensitivity to fork-stalling agents. Altogether, our findings suggest an important role of FEN1 succinylation in regulating its roles in DNA replication and repair, thus maintain genome stability.

中文翻译：

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FEN1关键残基的琥珀酰化作用涉及DNA损伤反应，以维持基因组稳定性。

人瓣内切核酸酶1（FEN1）是DNA复制和修复必不可少的结构特异性多功能核酸内切酶。我们以前的研究表明，针对DNA损伤，FEN1与PCNA样的Rad9-Rad1-Hus1复合体（而非PCNA）相互作用，参与DNA修复活动，例如停滞的DNA复制叉修复，并通过SUMO-1进行SUMOylation。在这里，我们报告说，FEN1的琥珀酰化反应是对DNA复制前叉试剂（例如紫外线，羟基脲，喜树碱和丝裂霉素C）的刺激而引起的。被甲基化抑制并被磷酸化刺激以促进SUMO-1修饰。FEN1 K200的琥珀酰化促进了FEN1与Rad9-Rad1-Hus1复合体的相互作用，以挽救停滞的复制叉。FEN1琥珀酰化的受损导致DNA损伤的积累，并增强了对前叉保鲜剂的敏感性。总之，我们的发现表明FEN1琥珀酰化在调节其在DNA复制和修复中的作用，从而维持基因组稳定性具有重要作用。