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很重要。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，表观遗传修饰剂如何与 DNA 修复机制协调以调节细胞放射敏感性相对未知。在这里，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 缺失增强了受照射的骨髓细胞和口腔黏膜上皮细胞的同源重组 (HR) 修复，但不增强非同源末端连接 (NHEJ) 修复。机理研究表明，RIOX1 去除了环状 GMP-AMP 合酶 (cGAS) K491 处的单甲基化，从而从其与甲基赖氨酸阅读器蛋白 SAGA 复合物相关因子 29 (SGF29) 的相互作用中释放出 cGAS，从而使 cGAS 与 poly( ADP-核糖基化聚（ADP-核糖）聚合酶 1 (PARP1) 在 DNA 断裂位点，从而阻止 PARP1 介导的 Timeless 募集。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。本研究强调了一种新的 RIOX1 依赖机制，该机制涉及 cGAS 的非免疫功能，这对于调节电离辐射引发的 HR 修复至关重要。随后使 cGAS 在 DNA 断裂位点与聚（ADP-核糖）化聚（ADP-核糖）聚合酶 1（PARP1）相互作用，从而阻止 PARP1 介导的 Timeless 募集。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。本研究强调了一种新的 RIOX1 依赖机制，该机制涉及 cGAS 的非免疫功能，这对于调节电离辐射引发的 HR 修复至关重要。随后使 cGAS 在 DNA 断裂位点与聚（ADP-核糖）化聚（ADP-核糖）聚合酶 1 (PARP1) 相互作用，从而阻止 PARP1 介导的 Timeless 募集。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。本研究强调了一种新的 RIOX1 依赖机制，该机制涉及 cGAS 的非免疫功能，这对于调节电离辐射引发的 HR 修复至关重要。