Xiao Yanxuan, Li Jingyi, Liao Xiaoyu, He Yumin, He Tao, Yang Cuiping, Jiang Lu, Jeon So Mi, Lee Jong-Ho, Chen Yongbin, Liu Rui, Chen Qianming
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610051, China.
Bone Res. 2022 Feb 24;10(1):19. doi: 10.1038/s41413-022-00194-0.
Exposure to radiation causes DNA damage; hence, continuous surveillance and timely DNA repair are important for genome stability. Epigenetic modifications alter the chromatin architecture, thereby affecting the efficiency of DNA repair. However, how epigenetic modifiers coordinate with the DNA repair machinery to modulate cellular radiosensitivity is relatively unknown. Here, we report that loss of the demethylase ribosomal oxygenase 1 (RIOX1) restores cell proliferation and reduces cell death after exposure to ionizing radiation. Furthermore, RIOX1 depletion enhances homologous recombination (HR) repair but not nonhomologous end-joining (NHEJ) repair in irradiated bone marrow cells and oral mucosal epithelial cells. Mechanistic study demonstrates that RIOX1 removes monomethylation at K491 of cyclic GMP-AMP synthase (cGAS) to release cGAS from its interaction with the methyl-lysine reader protein SAGA complex-associated factor 29 (SGF29), which subsequently enables cGAS to interact with poly(ADP-ribosyl)ated poly(ADP-ribose) polymerase 1 (PARP1) at DNA break sites, thereby blocking PARP1-mediated recruitment of Timeless. High expression of RIOX1 maintains cGAS K491me at a low level, which impedes HR repair and reduces cellular tolerance to ionizing radiation. This study highlights a novel RIOX1-dependent mechanism involved in the non-immune function of cGAS that is essential for the regulation of ionizing radiation-elicited HR repair.
暴露于辐射会导致DNA损伤；因此，持续监测和及时的DNA修复对于基因组稳定性至关重要。表观遗传修饰会改变染色质结构，从而影响DNA修复的效率。然而，表观遗传修饰因子如何与DNA修复机制协同调节细胞放射敏感性相对未知。在此，我们报告去甲基化酶核糖体加氧酶1（RIOX1）的缺失可恢复细胞增殖并减少暴露于电离辐射后的细胞死亡。此外，RIOX1的缺失增强了受辐射的骨髓细胞和口腔黏膜上皮细胞中的同源重组（HR）修复，但不影响非同源末端连接（NHEJ）修复。机制研究表明，RIOX1去除环状GMP-AMP合酶（cGAS）K491位点的单甲基化，使其从与甲基赖氨酸读取蛋白SAGA复合体相关因子29（SGF29）的相互作用中释放出来，随后cGAS能够在DNA断裂位点与多聚（ADP-核糖基）化的多聚（ADP-核糖）聚合酶1（PARP1）相互作用，从而阻止PARP1介导的Timeless招募。RIOX1的高表达使cGAS K491me维持在低水平，这会阻碍HR修复并降低细胞对电离辐射的耐受性。这项研究揭示了一种新的依赖RIOX1的机制，该机制参与cGAS的非免疫功能，对电离辐射引发的HR修复调节至关重要。
