RIOX1-demethylated cGAS regulates ionizing radiation-elicited DNA repair

Bone Res. 2022 Feb 24;10(1):19. doi: 10.1038/s41413-022-00194-0.

Yanxuan Xiao ^# ¹, Jingyi Li ^# ² ³, Xiaoyu Liao ¹, Yumin He ¹, Tao He ⁴, Cuiping Yang ⁵, Lu Jiang ¹, So Mi Jeon ⁶, Jong-Ho Lee ⁶ ⁷, Yongbin Chen ⁵ ⁸, Rui Liu ⁹, Qianming Chen ¹⁰

Affiliations

1 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.
2 The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610051, China.
3 School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610599, China.
4 Department of Cardio-thoracic Surgery, the Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610051, China.
5 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
6 Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea.
7 Department of Biological Sciences, Dong-A University, Busan, 49315, Republic of Korea.
8 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
9 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. [email protected].
10 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. [email protected].
# Contributed equally.

PMID: 35210392 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.

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