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Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair
Cell Metabolism ( IF 29.0 ) Pub Date : 2021-08-02 , DOI: 10.1016/j.cmet.2021.07.009
Rui Liu 1 , Jingyi Li 2 , Jichun Shao 3 , Jong-Ho Lee 4 , Xuemei Qiu 1 , Yanxuan Xiao 1 , Bowen Zhang 3 , Yilong Hao 5 , Mi Li 6 , Qianming Chen 1
Affiliation  

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.



中文翻译:

先天免疫反应协调磷酸核糖焦磷酸合成酶以支持 DNA 修复

电离辐射引起的 DNA 损伤会导致基因组不稳定并且具有高度细胞毒性。脱氧核糖核苷酸代谢为 DNA 修复提供了基础。然而,如何及时调节脱氧核糖核苷酸代谢以与 DNA 修复相协调仍然难以捉摸。在这里,我们显示电离辐射导致 TBK1 介导的磷酸核糖焦磷酸合成酶 (PRPS)1/2 在 T228 的磷酸化,从而增强 PRPS1/2 的催化活性并促进脱氧核糖核苷酸的合成。在电离辐射下 PRPS1/2 T228 磷酸化需要 DNA 损伤引发的 cGAS/STING 轴激活和 ATM 介导的 PRPS1/2 S16 磷酸化。此外,T228 磷酸化覆盖了变构调节剂介导的作用,并保留了高活性的 PRPS1/2。非磷酸化 PRPS1/2 突变体的表达或 cGAS/STING 轴的抑制会抵消电离辐射诱导的 PRPS1/2 活化、脱氧核糖核苷酸合成和 DNA 修复,并进一步损害细胞活力。这项研究强调了一种新的重要机制,这种机制是先天免疫反应引导的脱氧核糖核苷酸代谢,它支持 DNA 修复。

更新日期:2021-10-06
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