Pseudouridine-mediated translation control of mRNA by methionine aminoacyl tRNA synthetase. Pseudouridine-mediated translation control of mRNA by methionine aminoacyl tRNA synthetase

Modification of nucleotides within mRNA emerges as a key path for gene expression regulation. Pseudouridine is of the most common RNA modifications; however, only a few mRNA modifiers were identified to date, and no one mRNA pseudouridine reader is known. Here we applied a novel genome-wide approach to identify mRNA regions that are bound by yeast methionine aminoacyl tRNAMet synthetase (MetRS). We found a clear enrichment to regions that were described previously to contain pseudouridine Follow-up in vitro and in vivo analyses on a prime target (position 1074 within YEF3 mRNA) demonstrated the pseudouridine importance for MetRS binding. Furthermore, polysomal and protein analyses revealed that 1074 mediates translation. Modification of this site occurs presumably by Pus6, a pseudouridine synthetase known to modify MetRS cognate tRNA. Consistently, the deletion of Pus6 leads to a decrease in the MetRS association with both tRNAMet and YEF3 mRNA. Furthermore, while global protein synthesis decreases in pus6, translation of YEF3 increases. Together, our data imply that Pus6 ‘writes’ modifications on tRNA and mRNA, and both type of RNAs are ‘read’ by MetRS for translation regulation purposes. This represents a novel integrated path for writing and reading modifications on both tRNA and mRNA, which may lead to coordination between global and gene-specific translational response.