Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response
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 phe...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723004114 |
| _version_ | 1797844320435306496 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Rui Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:20:23Z |
| format | Article |
| id | doaj.art-43ba1906776541b1b50ade26663d94c9 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T17:20:23Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-43ba1906776541b1b50ade26663d94c92023-04-19T04:22:34ZengElsevierCell Reports2211-12472023-04-01424112400Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage responseRui Zhao0Ke Cai1Jing-Jing Yang2Qian Zhou3Wei Cao4Jie Xiang5Yi-Hui Shen6Lei-Lei Cheng7Wei-Dong Zang8Yan Lin9Yi-Yuan Yuan10Wei Xu11Hui Tao12Shi-Min Zhao13Jian-Yuan Zhao14Obstetrics & 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, ChinaInstitute 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, ChinaDepartment of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei 230601, ChinaObstetrics & 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, ChinaDepartment of Cardiothoracic Surgery, Second Hospital of Anhui Medical University, and Cardiovascular Research Center, Anhui Medical University, Hefei 230601, ChinaObstetrics & 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, ChinaObstetrics & 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, ChinaObstetrics & 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, ChinaSchool of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaObstetrics & 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, ChinaObstetrics & 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, ChinaObstetrics & 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, ChinaInstitute 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 authorObstetrics & 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 authorInstitute 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723004114CP: Molecular biology |
| spellingShingle | 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 Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response Cell Reports CP: Molecular biology |
| title | Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response |
| title_full | Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response |
| title_fullStr | Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response |
| title_full_unstemmed | Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response |
| title_short | Nuclear ATR lysine-tyrosylation protects against heart failure by activating DNA damage response |
| title_sort | nuclear atr lysine tyrosylation protects against heart failure by activating dna damage response |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723004114 |
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