{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe cytoplasmic valyl-tRNA synthetase (VARS1) is an essential enzyme that charges tRNA with valine to facilitate protein translation, and its proper function is critical for neurodevelopment. Recent clinical investigations have identified biallelic missense mutations in VARS1 that are linked to severe pediatric neurodevelopmental disorders, including global developmental delay, epileptic encephalopathy, and progressive microcephaly. Patient‐derived cells harboring these mutations exhibit markedly reduced enzyme activity and lower VARS1 mRNA and protein levels, underscoring its indispensability for normal brain growth and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \nDissecting the molecular architecture of VARS1 reveals that it forms part of a larger macromolecular complex. Structural studies have demonstrated that human VARS1 associates with elongation factor 1 (EF-1H) in a stable high-molecular mass assembly, with the complex adopting a dimeric, two-domain configuration that likely facilitates the efficient, consecutive steps of tRNA aminoacylation and subsequent protein elongation during translation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n\nMore recently, VARS1 has emerged as an important modulator in cancer biology. In the context of resistance to MAPK-targeted therapies in melanoma, upregulation of VARS1 and its associated increase in valine-specific tRNA levels have been implicated in a codon-biased translational reprogramming. This reprogramming favors the expression of key metabolic enzymes, such as those involved in fatty acid oxidation, thus promoting cell survival under therapeutic stress. Notably, knockdown of VARS1 re-sensitizes resistant melanoma cells both in vitro and in vivo, positioning this enzyme as a promising target in overcoming therapy-resistant malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jennifer Friedman, Desiree E Smith, Mahmoud Y Issa, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-018-1882-3"}], "href": "https://doi.org/10.1007/s00439-018-1882-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29691655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29691655"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Shoulei Jiang, Cindy L Wolfe, J Anthony Warrington, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Three-dimensional reconstruction of the valyl-tRNA synthetase/elongation factor-1H complex and localization of the delta subunit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2005.09.062"}], "href": "https://doi.org/10.1016/j.febslet.2005.09.062"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16229838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16229838"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41556-024-01439-2"}], "href": "https://doi.org/10.1038/s41556-024-01439-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38849541"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38849541"}]}]}]}