Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair
Résumé
Amino acid bioa v ailability impacts mRNA translation in a codon-dependent manner. Here, w e report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This coincides with the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate-and glutamaterich proteins, in v olv ed in DNA metabolism such as DNA replication and repair . Consequently , cells that survive MAPKi degrade aspartate and glutamate likely to generate energy, which simultaneously decreases their requirement for amino acids due to the downregulation of aspartateand glutamate-rich proteins in v olv ed in cell proliferation. Concomitantly, the downregulation of aspartate-and glutamate-rich proteins in v olv ed in DNA repair increases DNA damage loads. Thus, DNA repair defects, and therefore mutations, are at least in part a secondary effect of the met abolic adapt ation of cells exposed to MAPKi.
Origine | Fichiers éditeurs autorisés sur une archive ouverte |
---|---|
licence |