Deng Zhiwen, Long Caiyun, Han Shuzhen, Xu Zhishen, Hou Teng, Li Weili, Wang Xingwu, Liu Xiangyu
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China.
International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China; South China Hospital, Health Science Center, Shenzhen University, Shenzhen, China.
J Biol Chem. 2024 Nov;300(11):107823. doi: 10.1016/j.jbc.2024.107823. Epub 2024 Sep 27.
UHRF1 (Ubiquitin-like with PHD and Ring Finger domains 1) is a crucial E3 ubiquitin ligase and epigenetic regulator with pivotal roles in various biological processes, including the maintenance of DNA methylation, regulation of gene expression, and facilitation of DNA damage repair. In this study, we unveil that UHRF1 interacts with the nonhomologous end joining factor XLF (also known as Cernunnos) following DNA double strand breaks in HeLa cells. Furthermore, we demonstrate that UHRF1 catalyzes lysine 63-linked polyubiquitination of XLF, rather than lysine 48-linked polyubiquitination. Notably, this polyubiquitination of XLF by UHRF1 does not affect its protein stability; instead, it enhances the recruitment of XLF to the sites of DNA damage. These findings shed light on the role of UHRF1 as a novel regulator of DNA repair through XLF in tumor cells.
UHRF1（含PHD和环指结构域的类泛素蛋白1）是一种关键的E3泛素连接酶和表观遗传调节剂，在多种生物学过程中发挥着关键作用，包括维持DNA甲基化、调节基因表达以及促进DNA损伤修复。在本研究中，我们揭示了在HeLa细胞中DNA双链断裂后，UHRF1与非同源末端连接因子XLF（也称为Cernunnos）相互作用。此外，我们证明UHRF1催化XLF的赖氨酸63连接的多聚泛素化，而非赖氨酸48连接的多聚泛素化。值得注意的是，UHRF1对XLF的这种多聚泛素化并不影响其蛋白质稳定性；相反，它增强了XLF向DNA损伤位点的募集。这些发现揭示了UHRF1作为肿瘤细胞中通过XLF对DNA修复的新型调节因子的作用。
