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EMBO Mol Med. 2020 Jan 31:e9469. doi: 10.15252/emmm.201809469. [Epub ahead of print]

Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.

Mei X1,2,3,4, Qi D1,5, Zhang T1,6, Zhao Y1,2,7, Jin L1,2, Hou J8, Wang J6, Lin Y1,2,4, Xue Y9, Zhu P8, Liu Z9, Huang L1,2, Nie J1,2, Si W8, Ma J10, Ye J1,2, Finnell RH11, Saiyin H1, Wang H1,2, Zhao J1,2,4, Zhao S1,2,4, Xu W1,2,4.

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State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.
NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China.
Capital Institute of Pediatrics, Beijing, China.
Shanghai Laboratory Animal Research Center, Shanghai, China.
Department of Chemistry, Fudan University, Shanghai, China.
Department of Medical Engineering, College of Life Sciences and Technology, Huazhong University of Science and Technology, Wuhan, China.
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Center for Precision Environmental Health, Departments of Molecular and Human Genetics, Molecular & Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX, USA.


Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases.


N-homocysteinylation; acetyl homocysteine thioether; methionyl-tRNA synthetase; neural tube defects; reactive oxygen species

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