# Mistranslating tRNA variants impact the proteome and phosphoproteome of Saccharomyces cerevisiae

## TL;DR

The study explores how mistranslating tRNA variants affect the proteome and phosphoproteome in yeast, revealing impacts on key cellular processes.

## Contribution

The paper provides a detailed phosphoproteomic and proteomic analysis of the effects of mistranslating tRNA variants in yeast.

## Key findings

- Mistranslating tRNAs modestly impact the proteome but influence key pathways like proteostasis and cell cycle.
- Phosphoproteome changes were significant, indicating altered signaling and regulation due to mistranslation.
- Growth defects and proteome changes varied depending on the tRNA substitution type.

## Abstract

Transfer RNAs (tRNAs) ensure accurate decoding of the genetic code. However, mutations in tRNAs can lead to misincorporation of an amino acid that differs from the genetic message in a process known as mistranslation. As mistranslating tRNAs modify how the genetic message is decoded, they have potential as therapeutic tools for diseases caused by nonsense and missense mutations. Despite this, they also produce proteome-wide mismade proteins, which can disrupt proteostasis. To better understand the impact of mistranslating tRNA variants, we profile the proteome and phosphoproteome of yeast expressing three different mistranslating tRNAs. While the overall impacts were similar, the extent of growth defects and proteome changes varied with the substitution type. Although the global impacts were modest, mistranslation influenced key cellular processes, including proteostasis, cell cycle, and translation. These findings highlight the need to consider cellular consequences when developing mistranslating tRNAs for therapeutic applications.

Using quantitative proteomics and phosphoproteomics, Berg et al. profile the cellular response of yeast to three different mistranslating tRNA variants. The authors find that although global proteome impacts were modest, mistranslating tRNAs affect protein abundance and phosphorylation in key pathways including proteostasis, cell cycle regulation, and translation. The dataset uncovers many changes, particularly in the phosphoproteome, that merit further investigation and provides a resource for understanding how mistranslation shapes cellular pathways. These findings underscore the importance of considering cellular consequences when engineering tRNAs for therapeutic applications and will be of interest to researchers studying tRNA biology, proteostasis, and regulation of translation fidelity.