Aminoacyl-tRNA Synthetases (ARSs) acylate tRNAs with amino acids. Charging tRNAs with the right amino acids is the first step in translation; therefore, the accurate and error-free functioning of ARSs is an essential prerequisite for translational fidelity. A recent study found that methionine (Met) can be incorporated into non-Met residues of proteins through methionylation to non-cognate tRNAs under oxidative stress. However, it was not understood how this mis-methionylation is achieved. Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK) upon reactive oxygen species (ROS) stress, and that this phosphorylated MRS showed increased affinity to non-cognate tRNAs with lower affinity to tRNA(Met), leading to an increase in Met residues in cellular proteins. The expression of a mutant MRS containing the substitutions S209D and S825D, mimicking dual phosphorylation, reduced ROS levels and cell death. This controlled inaccuracy of MRS seems to serve as a defense mechanism against ROS-mediated damage at the cost of translational fidelity.
Lee, J. Y., Kim, D. G., Kim, B.-G., Yang, W. S., Hong, J., Kang, T., … Kim, S. (2014). Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. Journal of Cell Science, 127(19), 4234–4245. https://doi.org/10.1242/jcs.152470