Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape.

Xueliang Lyu,She Chen,Qian Yang,Yi Liu,Lin Li,Zhipeng Zhou,Yunkun Dang,Michael Freitag

doi:10.1371/journal.pgen.1008836

Abstract

Codon usage bias is a universal feature of all genomes and plays an important role in regulating protein expression levels. Modification of adenosine to inosine at the tRNA anticodon wobble position (I34) by adenosine deaminases (ADATs) is observed in all eukaryotes and has been proposed to explain the correlation between codon usage and tRNA pool. However, how the tRNA pool is affected by I34 modification to influence codon usage-dependent gene expression is unclear. Using Neurospora crassa as a model system, by combining molecular, biochemical and bioinformatics analyses, we show that silencing of adat2 expression severely impaired the I34 modification levels for the ADAT-related tRNAs, resulting in major ADAT-related tRNA profile changes and reprogramming of translation elongation kinetics on ADAT-related codons. adat2 silencing also caused genome-wide codon usage-biased ribosome pausing on mRNAs and proteome landscape changes, leading to selective translational repression or induction of different mRNAs. The induced expression of CPC-1, the Neurospora ortholog of yeast GCN4p, mediates the transcriptional response after adat2 silencing and amino acid starvation. Together, our results demonstrate that the tRNA I34 modification by ADAT plays a major role in driving codon usage-biased translation to shape proteome landscape.

Highlights

In eukaryotes, more than 50 different chemical modifications at different positions of transfer RNA (tRNA) have been described (RNA modification database https://mods.rna.albany.edu/) [1]
Biochemical and bioinformatics analyses, we showed that the correlation between genome codon usage and tRNA I34 modification modulates translation elongation kinetics and proteome
There are no tRNAs with ANN anticodons, and the tRNAs with GNN anticodons are dominant; decoding of NNU codons depends on tRNAs that can form G:U wobble at the third position of codon-anticodon interaction

Summary

Introduction

More than 50 different chemical modifications at different positions of tRNAs have been described (RNA modification database https://mods.rna.albany.edu/) [1]. These modifications are important for tRNA structure, function, and stability, and some modifications have been shown to impact codon-biased protein expression [2,3,4,5,6]. A positive correlation between codon usage bias and transfer RNA (tRNA) expression is thought to allow genes with more optimal codons to be more efficiently translated than those enriched with rare codons [17,24,25,26,27,28,29,30].

Methods

Results

Discussion

Conclusion