RIOX1-demethylated cGAS regulates ionizing radiation-elicited DNA repair

Yanxuan Xiao,Jingyi Li,Lu Jiang,Jong-Ho Lee,Yumin He,Cuiping Yang,So Mi Jeon,Qianming Chen,Yongbin Chen,Tao He,Rui Liu,Xiaoyu Liao

doi:10.1038/s41413-022-00194-0

Abstract

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.

Highlights

We report a novel RIOX1mediated mechanism that modulates the efficiency of homologous recombination (HR) repair
We demonstrate that ribosomal oxygenase 1 (RIOX1) abolishes the monomethylation of K491 in cyclic GMPAMP synthase, which disrupts the interaction between cyclic GMP-AMP synthase (cGAS) and the methyllysine reader protein SAGA complex-associated factor 29 (SGF29). cGAS without K491me binds to poly(ADP-ribosyl)ated poly(ADPribose) polymerase 1 and abrogates the recruitment of Timeless to DNA break sites, thereby blocking HR repair
0.65 kb 0.5 kb RESULTS RIOX1 decreases cell viability and inhibits HR repair in bone marrow cells after ionizing radiation To evaluate the effects of RIOX1 on bone marrow cells after ionizing radiation, RIOX1 knockout mice were examined

Summary

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Exposure to ionizing radiation may cause both acute symptoms and long-term health effects.[1]. The bone marrow is the most vulnerable to ionizing radiation-induced damage due to the rapid turnover of immature hematopoietic cells. HR repair of damaged sites involves template-guided DNA extension, which guarantees error-free repair by restoring sequence information from the templates. Ribosomal oxygenase 1 (RIOX1) removes mono- or trimethylation from histone 3 lysine 4 (H3K4me[1] or H3K4me[3], respectively), while it has weaker activity toward methylated H3K36.9 whether RIOX1 is involved in DNA repair upon ionizing radiation-induced damage is largely undefined. We show that depletion of RIOX1 in mouse bone marrow cells restores cell viability and decreases cell death upon exposure to ionizing radiation. CGAS without K491me binds to poly(ADP-ribosyl)ated poly(ADPribose) polymerase 1 and abrogates the recruitment of Timeless to DNA break sites, thereby blocking HR repair. RIOX1 regulates cGAS and BM cell radiosensitivity Y Xiao et al

RESULTS

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DISCUSSION