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Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia\u2010associated pathologies. Herein, we report the potential roles of methionyl\u2010tRNA synthetase (MARS)\u2010generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of\n                    <jats:italic>MARS<\/jats:italic>\n                    and\/or\n                    <jats:italic>MARS2<\/jats:italic>\n                    were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)\u2010homocysteinylation. Here, we identified hundreds of novel N\u2010homocysteinylated proteins. N\u2010homocysteinylation of superoxide dismutases (SOD1\/2) provided new mechanistic insights for homocysteine\u2010induced 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\u2010induced and hyperhomocysteinemia\u2010induced 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\u2010associated diseases.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201809469","type":"journal-article","created":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T03:40:37Z","timestamp":1580442037000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Inhibiting MARSs reduces hyperhomocysteinemia\u2010associated neural tube and congenital heart defects"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2637-795X","authenticated-orcid":false,"given":"Xinyu","family":"Mei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dashi","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junli","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9403-6869","authenticated-orcid":false,"given":"Yu","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-0610","authenticated-orcid":false,"given":"Zexian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Si","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhong","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5962-8754","authenticated-orcid":false,"given":"Richard H","family":"Finnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hexige","family":"Saiyin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9422-5264","authenticated-orcid":false,"given":"Hongyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4309-8787","authenticated-orcid":false,"given":"Shimin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9858-589X","authenticated-orcid":false,"given":"Wei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,31]]},"reference":[{"key":"BFEMMM201809469_CR1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1258\/acb.2009.008207","volume":"46","author":"DJ Bakker","year":"2009","unstructured":"Bakker DJ, de Jong\u2010van den Berg LT, Fokkema MR (2009) Controlled study on folate status following folic acid supplementation and discontinuation in women of child\u2010bearing age. 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