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

Abstract

Transfer RNAs (tRNAs) are heavily decorated with post-transcriptional chemical modifications. Approximately 100 different modifications have been identified in tRNAs, and each tRNA typically contains 5–15 modifications that are incorporated at specific sites along the tRNA sequence. These modifications may be classified into two groups according to their position in the three-dimensional tRNA structure, i.e., modifications in the tRNA core and modifications in the anticodon-loop (ACL) region. Since many modified nucleotides in the tRNA core are involved in the formation of tertiary interactions implicated in tRNA folding, these modifications are key to tRNA stability and resistance to RNA decay pathways. In comparison to the extensively studied ACL modifications, tRNA core modifications have generally received less attention, although they have been shown to play important roles beyond tRNA stability. Here, we review and place in perspective selected data on tRNA core modifications. We present their impact on tRNA structure and stability and report how these changes manifest themselves at the functional level in translation, fitness and stress adaptation.

Trypanosoma brucei multi-aminoacyl-tRNA synthetase complex formation limits promiscuous tRNA proofreading

“…Other factors that could offer tRNA Ala protection from MCP3 are tRNA modifications and the presence of other modified tRNA species. An open question in the field of trans -editing factors is whether tRNA modifications act as anti-determinants for proofreading ( Giegé and Eriani, 2023 ; Yared et al, 2024 ). Future work will determine the impact of the Tb MCP3 interactome and the role of post-transcriptional/translational modifications on the activity of this editing domain.…”

Tuning tRNAs for improved translation

“…tRNAs are frequently post-transcriptionally imbued with diverse modifications that drastically impact their structure and function ( Lorenz et al, 2017 ; Suzuki, 2021 ; Cappannini et al, 2024 ; Yared et al, 2024 ). tRNAs exhibit diverse modifications in all arms, but they are most frequent at the tRNA core and anticodon arm ( Cantara et al, 2011 ; Smith et al, 2024 ).…”

“…In fact, tRNAs are the most extensively modified cellular RNA with about 12% of nucleotides modified (an average of eight modifications per bacterial tRNA and 13 per eukaryotic ( Zhang et al, 2022 ) and around 100 distinct modifications identified in total ( Machnicka et al, 2014 ; Cappannini et al, 2024 ). Some bases like the 3′ CCA end and discriminator base are never modified, while others are modification hotspots, such as nucleotides in the elbow region ( Yared et al, 2024 ) and anticodon loop ( Lorenz et al, 2017 ).…”