Control of translation by tRNA-like elements within the mRNA

Translation regulation is exerted through the function of large collection of mRNA binding proteins (RBPs) that interact with target elements within the mRNA and alter ribosomal association. Recent interactome studies had identified many novel RBPs that are likely to interact through yet unknown RNA features. A prominent group of such novel RBPs are the family of aminoacyl tRNA synthetases, well known for their binding to another type of RNA, tRNA. To identify the targets of this family of enzymes, we performed a comprehensive analysis of mRNAs bound by almost all yeast cytosolic tRNA synthetases. This analysis suggested binding to structural features that resemble anticodon stem-loop (ASL) of cognate tRNAs. To further characterize these ASL-like features, we investigated an ASL mimic within histidine synthetase target mRNA. Point mutations in this element abolished binding and led to increased translation of the target mRNA. Notably, overexpression of tRNA^His also reduced mRNA binding, suggesting coordination between tRNA levels and mRNA binding. Next, we performed an unbiased screen for possible elements that are bound by threonine tRNA synthetase. Random bases were introduced into an mRNA target of this synthetase; notably, the top bound sequence was similar to the ASL of tRNA^Thr. Furthermore, translation level of a target mRNA that included this ASL-mimic was significantly higher compared to a variant that contained a distorted structure. Overall, our data reveal a key role for tRNA anticodon stem-loop-like elements within mRNA in translation regulation.