Niida Hiroyuki, Ito Masahiko, Iijima Kenta, Motegi Akira, Ogihara Rin, Akiyama Hironobu, Uchida Chiharu, Sakai Satoshi, Ohhata Tatsuya, Hatano Atsushi, Hirose Michiko, Ogura Atsuo, Matsumoto Masaki, McDonald Neil Q, Kitagawa Masatoshi
Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan.
Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
Nucleic Acids Res. 2025 Apr 22;53(8). doi: 10.1093/nar/gkaf355.
The structure-specific endonuclease, XPF-ERCC1, plays a central role in DNA damage repair. This nuclease is known to be important for nucleotide excision repair, interstrand crosslink repair, and DNA double-strand repair. We found that the arginine methyltransferase, CARM1/PRMT4, is essential for XPF stabilization and maintenance of intracellular protein levels. Loss of CARM1 results in a decrease in XPF protein levels and a concomitant decrease in ERCC1 protein. A similar destabilization of XPF protein was observed in cells expressing a mutant in which XPF arginine 568 was replaced by lysine. Loss of CARM1 impaired XPF-ERCC1 accumulation at the site of damage and delayed removal of cyclobutane pyrimidine dimers by UV. As a result, CARM1-deficient cells showed increased UV sensitivity. Our results provide insight into the importance of CARM1 not only in the mechanism of XPF-ERCC1 complex stabilization but also in the maintenance of genome stability.
结构特异性核酸内切酶XPF-ERCC1在DNA损伤修复中起核心作用。已知这种核酸酶对核苷酸切除修复、链间交联修复和DNA双链修复很重要。我们发现精氨酸甲基转移酶CARM1/PRMT4对XPF的稳定及细胞内蛋白质水平的维持至关重要。CARM1缺失导致XPF蛋白水平降低，同时ERCC1蛋白也减少。在表达XPF精氨酸568被赖氨酸取代的突变体的细胞中，观察到XPF蛋白有类似的不稳定情况。CARM1缺失会损害XPF-ERCC1在损伤位点的积累，并延迟紫外线诱导的环丁烷嘧啶二聚体的去除。因此，CARM1缺陷细胞对紫外线的敏感性增加。我们的结果不仅揭示了CARM1在XPF-ERCC1复合物稳定机制中的重要性，还揭示了其在维持基因组稳定性方面的重要性。
