Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response
Rui Zhao,
Ke Cai,
Jing-Jing Yang,
Qian Zhou,
Wei Cao,
Jie Xiang,
Yi-Hui Shen,
Lei-Lei Cheng,
Wei-Dong Zang,
Yan Lin,
Yi-Yuan Yuan,
Wei Xu,
Hui Tao,
Shi-Min Zhao,
Jian-Yuan Zhao
Affiliations
Rui Zhao
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China; Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Ke Cai
Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Jing-Jing Yang
Department of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China
Qian Zhou
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Wei Cao
Department of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China
Jie Xiang
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
Yi-Hui Shen
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
Lei-Lei Cheng
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
Wei-Dong Zang
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
Yan Lin
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
Yi-Yuan Yuan
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
Wei Xu
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
Hui Tao
Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China; Corresponding author
Shi-Min Zhao
Obstetrics & Gynecology Hospital of Fudan University, Zhongshan Hospital of Fudan University, State Key Laboratory of Genetic Engineering, School of Life Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China; Corresponding author
Jian-Yuan Zhao
Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei 230601, China; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Corresponding author
Summary: 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.
