Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response

作者：Rui Zhao, Ke Cai, Jingjing Yang, Qian Zhou, Wei Cao, Jie Xiang, Yihui Shen, Leilei Cheng, Weidong Zang, Yan Lin, Yiyuan Yuan, Wei Xu, Hui Tao, Shimin Zhao, Jian‐Yuan Zhao · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.112400 · 被引用次数：21 · 研究领域：Sirtuins and Resveratrol in Medicine、Metabolomics and Mass Spectrometry Studies、RNA and protein synthesis mechanisms

Dysregulated amino acid increases the risk for heart failure (HF) via unclear mechanisms. Here, we find that increased plasma tyrosine and phenylalanine levels are associated with HF. Increasing tyrosine or phenylalanine by high-tyrosine or high-phenylalanine chow feeding exacerbates HF phenotypes in transverse aortic constriction and isoproterenol infusion mice models. Knocking down phenylalanine dehydrogenase abolishes the effect of phenylalanine, indicating that phenylalanine functions by converting to tyrosine. Mechanistically, tyrosyl-tRNA synthetase (YARS) binds to ataxia telangiectasia and Rad3-related gene (ATR), catalyzes lysine tyrosylation (K-Tyr) of ATR, and activates the DNA damage response (DDR) in the nucleus. Increased tyrosine inhibits the nuclear localization of YARS, inhibits the ATR-mediated DDR, accumulates DNA damage, and elevates cardiomyocyte apoptosis. Enhancing ATR K-Tyr by overexpressing YARS, restricting tyrosine, or supplementing tyrosinol, a structural analog of tyrosine, promotes YARS nuclear localization and alleviates HF in mice. Our findings implicate facilitating YARS nuclear translocation as a potential preventive and/or interfering measure against HF.