Annuaire
Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair.
NAR Cancer, 6(2):zcae019.
Amino acid bioavailability impacts mRNA translation in a codon-dependent manner.Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease theintracellular concentration of aspartate and glutamate in melanoma cells. Thiscoincides with the accumulation of ribosomes on codons corresponding to theseamino acids and triggers the translation-dependent degradation of mRNAs encodingaspartate- and glutamate-rich proteins, involved in DNA metabolism such as DNAreplication and repair. Consequently, cells that survive MAPKi degrade aspartateand glutamate likely to generate energy, which simultaneously decreases theirrequirement for amino acids due to the downregulation of aspartate- andglutamate-rich proteins involved in cell proliferation. Concomitantly, thedownregulation of aspartate- and glutamate-rich proteins involved in DNA repairincreases DNA damage loads. Thus, DNA repair defects, and therefore mutations,are at least in part a secondary effect of the metabolic adaptation of cellsexposed to MAPKi.
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