Human TRMT2A methylates tRNA and contributes to translation fidelity

Abstract

5-Methyluridine (m5U) is one of the most abundant RNA modifications found in cytosolic tRNA. tRNA methyltransferase 2 homolog A (hTRMT2A) is the dedicated mammalian enzyme for m5U formation 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 hTRMT2A is achieved by a combination of modest binding preference and presence of a uridine in position 54 of tRNAs. Mutational analysis together with cross-linking experiments identified a large hTRMT2A–tRNA binding surface. Furthermore, complementing hTRMT2A interactome studies revealed that hTRMT2A interacts with proteins involved in RNA biogenesis. Finally, we addressed the question of the importance of hTRMT2A function by showing that its knockdown reduces translation fidelity. These findings extend the role of hTRMT2A beyond tRNA modification towards a role in translation.

Modifications in the T arm of tRNA globally determine tRNA maturation, function and cellular fitness

“…The human homologs, TRMT2A and TRUB1 have also been implicated in modulating protein synthesis. Although human TRMT2A does not affect synthesis of polyQ proteins, the aggregation of polyQ is reduced 19 and translation fidelity is decreased in the absence of TRMT2A 40 . Moreover, human TRUB1 affects mitochondrial tRNA conformation and mitochondrial translation thus decreasing the assembly and activity of oxidative phosphorylation complexes, without altering tRNA abundance 21 .…”

Beyond the Anticodon: tRNA Core Modifications and Their Impact on Structure, Translation and Stress Adaptation

“…In yeast, there is a slight global increase in the translation efficiency in trm2 strains lacking m 5 U54 [ 137 ]. It is also worth mentioning that in humans, the m 5 U54 modification appears to be involved in translation fidelity [ 138 ].…”