biostudies-literatureEl-Hachem NWorldwide Cancer Research1154-1164https://www.ebi.ac.uk/biostudies/studies/S-EPMC11252002biostudies-literatureUnknown26(7)Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, amoNature cell biologyValine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.PMC1125200223-0288Marine JCTarassov IRoncarati PCapron CBlomme AEl-Hachem NAgami RNguyen LTurchetto SLavergne AThandapani PMartin-Morales LGoffin EPirotte BClose PRapino FLeclercq MSusaeta Ruiz MVanleyssem RShostak KKorner PRChariot AHerfs MfalseValine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma.Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, amo2024-01-01T00:00:00Z2024 Jul2026-06-02T09:28:54.89Z2025-04-06T12:33:27.832ZS-EPMC112520023884954110.1038/s41556-024-01439-2