Transcriptome-wide Analysis of Roles for tRNA Modifications in Translational Regulation

Abstract

SUMMARY Covalent nucleotide modifications in noncoding RNAs affect a plethora of biological processes, and new functions continue to be discovered even for well-known modifying enzymes. To systematically compare the functions of a large set of ncRNA modifications in gene regulation, we carried out ribosome profiling in budding yeast to characterize 57 nonessential genes involved in tRNA modification. Deletion mutants exhibited a range of translational phenotypes, with enzymes known to modify anticodons, or non-tRNA substrates such as rRNA, exhibiting the most dramatic translational perturbations. Our data build on prior reports documenting translational upregulation of the nutrient-responsive transcription factor Gcn4 in response to numerous tRNA perturbations, and identify many additional translationally-regulated mRNAs throughout the yeast genome. Our data also uncover unexpected roles for tRNA modifying enzymes in regulation of TY retroelements, and in rRNA 2′-O-methylation. This dataset should provide a rich resource for discovery of additional links between tRNA modifications and gene regulation.

Queuosine‐modified tRNAs confer nutritional control of protein translation

“…In our Q-free cell culture system and mouse model, dysregulation of translation resulted in the accumulation of misfolded proteins and aggregates that trigger the activation of ER stress and the UPR. This mechanism is in agreement with the phenotypes recently described in mouse and yeast that lack certain modifications at the wobble position (Laguesse et al, 2015;Chou et al, 2017).…”

“…In particular, position 34 is subject to various modifications (Agris et al , ), depending on the associated tRNA isoacceptor and the organism (Grosjean et al , ; El Yacoubi et al , ). Some of these modifications have been shown to be important for the fine‐tuning of protein translation and for the maintenance of proteome integrity in yeast and in C. elegans (Rezgui et al , ; Zinshteyn & Gilbert, ; Nedialkova & Leidel, ; Chou et al , ).…”

RNAs, Phase Separation, and Membrane‐Less Organelles: Are Post‐Transcriptional Modifications Modulating Organelle Dynamics?

“…Curiously, many RNA modification systems appear not to be essential for life since organisms with mutations in the responsible activities are viable and fertile. However, combining different RNA modification system mutations or exposing particular RNA modification system mutants to non‐standard laboratory conditions (i.e., stress) caused observable phenotypes indicating that the biological function of many RNA modifications has to be sought in the response to environmental insults . Indeed, recent research showed that RNA modification patterns can change, especially during the response to particular stresses resulting, for instance, in the reprogramming of protein translation .…”

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…The m2,2G modification could also play a role in proper tRNA interaction with the ribosome to ensure efficient translation. Indeed, studies in yeast S. cerevisiae have found that Trm1 deletion mutants display alterations in ribosome profiles indicative of translation aberrations (Chou, Donnard, Gustafsson, Garber, & Rando, 2017). Moreover, studies in human cells have found that global translation is reduced upon ablation of TRMT1 (Dewe et al, 2017).…”