To be or not to be modified: Miscellaneous aspects influencing nucleotide modifications in tRNAs

Abstract

Transfer RNAs (tRNAs) are essential components of the cellular protein synthesis machineries, but are also implicated in many roles outside translation. To become functional, tRNAs, initially transcribed as longer precursor tRNAs, undergo a tightly controlled biogenesis process comprising the maturation of their extremities, removal of intronic sequences if present, addition of the 3′‐CCA amino‐acid accepting sequence, and aminoacylation. In addition, the most impressive feature of tRNA biogenesis consists in the incorporation of a large number of posttranscriptional chemical modifications along its sequence. The chemical nature of these modifications is highly diverse, with more than hundred different modifications identified in tRNAs to date. All functions of tRNAs in cells are controlled and modulated by modifications, making the understanding of the mechanisms that determine and influence nucleotide modifications in tRNAs an essential point in tRNA biology. This review describes the different aspects that determine whether a certain position in a tRNA molecule is modified or not. We describe how sequence and structural determinants, as well as the presence of prior modifications control modification processes. We also describe how environmental factors and cellular stresses influence the level and/or the nature of certain modifications introduced in tRNAs, and report situations where these dynamic modulations of tRNA modification levels are regulated by active demodification processes. © 2019 IUBMB Life, 71(8):1126–1140, 2019

Time-resolved NMR monitoring of tRNA maturation

“…This family not only displays the largest variety of posttranscriptional decorations among RNA molecules, but also the highest density of modifications per RNA transcript (3,4). The introduction of post-transcriptional chemical modifications is central in the maturation process to generate functional tRNA molecules (5)(6)(7). The biogenesis of tRNAs is a multistep process that comprises the synthesis of a tRNA precursor (pre-tRNA) by transcription of a tRNA gene, the removal of the 5'-leader and 3'-trailer sequences, the addition of the 3'-CCA amino-acid accepting sequence, the removal of intronic sequences when present, and the incorporation of a large number of post-transcriptional chemical modifications (8).…”

“…While modified nucleotides in the ACL participate in decoding during protein synthesis (11,12), those in the tRNA core are collectively implicated in the folding and stability of tRNAs (13). While a simple model would be that modifications are introduced to tRNA independently, several modification circuits have been identified in which one or more modifications stimulate formation of a subsequent modification (7,14). This obviously drives a defined sequential order in the tRNA modification process.…”

“…This obviously drives a defined sequential order in the tRNA modification process. In addition, the interdependence of multiple modification events might in certain cases be responsible for the variations of tRNA modifications in response to environmental perturbations (2,7,(15)(16)(17). The characterization of modification circuits is therefore central to understand the dynamic regulation of modifications in tRNAs, however their identification remains difficult since monitoring tRNA maturation at a single nucleotide level in a time-resolved fashion is technically challenging (18).…”

Broad-range RNA modification analysis of complex biological samples using rapid C18-UPLC-MS

“…As cells grow, nutrients become increasingly scarce and potentially toxic metabolic byproducts become more abundant, creating an imbalance that causes nutritional stress. Biotic stress is reflected in tRNA modification levels as protein synthesis must adapt to maintain cellular homeostasis [44][45][46][47][48] .…”

S-adenosylmethionine tRNA modification: unexpected/unsuspected implications of former/new players

“…tRNA processing is carried out with very complex and intricate mechanisms, most likely because we do not understand all the regulatory steps that take place in this system; for example, post-transcriptional modifications appear across the entire process before or after the processing of the extremities and before or after the removal of the introns [8]. Many of these modifications are introduced to tRNA independently; however, several of them are interconnected with a modification that drives the formation of following one [8].…”