Human TRMT2A methylates tRNA and contributes to translation fidelity

Abstract

Methyl-5-uridine (m5U) is one of the most abundant RNA modifications found in cytosolic tRNA. tRNA methyltransferase 2 homolog A (hTRMT2A) is the dedicated mammalian enzyme of m5U conversion at tRNA position 54. However, its RNA binding specificity and functional role in the cell are not well understood. Here we dissected structural and sequence requirements for binding and methylation of its RNA targets. Specificity of tRNA modification by TRMT2A is achieved by a combination of modest binding preference and presence of a uridine in position 54 of tRNAs. Mutational analysis together with crosslinking experiments identified a large hTRMT2A-tRNA binding surface. Furthermore, complementing hTRMT2A interactome studies revealed that TRMT2A interacts with proteins involved in both tRNA and rRNA biogenesis. Consistent with this finding, we observed that TRMT2A not only methylates tRNA, but also rRNA. Finally, we addressed the question of the importance of TRMT2A function by showing that its knockdown reduces translational fidelity. These findings extend the role of hTRMT2A beyond tRNA modification towards rRNA biogenesis and translational fidelity.

The Pros of changing tRNA identity

“…Advances in high-resolution methodologies that detect mistranslation ( 9 ) will offer unprecedented opportunities to uncover new mistranslation events and to better understand how they promote cell growth and adaptation. There are also important therapeutic implications for directed mistranslation, for example in developing treatments for poly-glutamine aggregation disorders ( 10 ). Where this will lead is fascinating to contemplate; as the philosopher Plutarch once said, “from their errors and mistakes the wise and good learn wisdom for the future”.…”