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  3. Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair

Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair

  • Cell Metab. 2021 Oct 5;33(10):2076-2089.e9. doi: 10.1016/j.cmet.2021.07.009.
Rui Liu 1,  Jingyi Li 2,  Jichun Shao 3,  Jong-Ho Lee 4,  Xuemei Qiu 5,  Yanxuan Xiao 5,  Bowen Zhang 3,  Yilong Hao 6,  Mi Li 7,  Qianming Chen 8
Affiliations

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. Electronic address: liurui_scu@hotmail.com.
  • 2 The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, China; School of Biological Sciences and Technology, Chengdu Medical College, Chengdu 610599, China.
  • 3 The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan 610051, China.
  • 4 Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Republic of Korea; Department of Biological Sciences, Dong-A University, Busan 49315, Republic of Korea.
  • 5 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.
  • 6 Key Laboratory of Oral Biomedical Research of Zhejiang Province, and the Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
  • 7 UTHealth Graduate School of Biomedical Sciences, Houston, TX 77225, USA.
  • 8 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. Electronic address: qmchen@scu.edu.cn.
PMID: 34343500 DOI: 10.1016/j.cmet.2021.07.009
Abstract

Ionizing radiation-induced DNA damages cause genome instability and are highly cytotoxic. Deoxyribonucleotide metabolism provides building blocks for DNA repair. Nevertheless, how deoxyribonucleotide metabolism is timely regulated to coordinate with DNA repair remains elusive. Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis. DNA damage-elicited activation of cGAS/STING axis and ATM-mediated PRPS1/2 S16 phosphorylation are required for PRPS1/2 T228 phosphorylation under ionizing radiation. Furthermore, T228 phosphorylation overrides allosteric regulator-mediated effects and preserves PRPS1/2 with high activity. The expression of non-phosphorylatable PRPS1/2 mutants or inhibition of cGAS/STING axis counteracts ionizing radiation-induced PRPS1/2 activation, deoxyribonucleotide synthesis, and DNA repair, and further impairs cell viability. This study highlights a novel and important mechanism underlying an innate immune response-guided deoxyribonucleotide metabolism, which supports DNA repair.

Keywords

ATM; DNA repair; STING; TBK1; cGAS; innate immune; ionizing radiation; nucleotide metabolism; phosphoribosyl pyrophosphate synthetase.

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