Abstract
In eukaryotes, the wobble position of tRNA with a GUN anticodon is modified to the 7-deaza-guanosine derivative queuosine (Q34), but the original source of Q is bacterial, since Q is synthesized by eubacteria and salvaged by eukaryotes for incorporation into tRNA. Q34 modification stimulates Dnmt2/Pmt1-dependent C38 methylation (m5C38) in the tRNAAsp anticodon loop in Schizosaccharomyces pombe. Here, we show by ribosome profiling in S. pombe that Q modification enhances the translational speed of the C-ending codons for aspartate (GAC) and histidine (CAC) and reduces that of U-ending codons for asparagine (AAU) and tyrosine (UAU), thus equilibrating the genome-wide translation of synonymous Q codons. Furthermore, Q prevents translation errors by suppressing second-position misreading of the glycine codon GGC, but not of wobble misreading. The absence of Q causes reduced translation of mRNAs involved in mitochondrial functions, and accordingly, lack of Q modification causes a mitochondrial defect in S. pombe. We also show that Q-dependent stimulation of Dnmt2 is conserved in mice. Our findings reveal a direct mechanism for the regulation of translational speed and fidelity in eukaryotes by a nutrient originating from bacteria.
Highlights
Fine-tuning of protein translation is crucial for rapid, accurate and efficient production of proteins
To investigate translational effects in vivo, ribosome profiling was performed with S. pombe cells [24,26]
The individual and combined effects of Dnmt2-dependent m5C38 methylation and queuosinylation of tRNAs were determined for wild-type and pmt1Δ cells that were cultured in the presence or absence of queuine
Summary
Fine-tuning of protein translation is crucial for rapid, accurate and efficient production of proteins. Each codon in an mRNA is decoded in the acceptor (A–) site of the ribosome via an interaction between the codon and the anticodon of the matching tRNA The optimization of this process is influenced by many factors, including the abundance of tRNAs, the usage of synonymous codons, the strength of the codon–anticodon interaction and interactions between the ribosome and the codon– anticodon complex [1,2]. A novel representation of the genetic code has been proposed, which takes energy-driven as well as structural aspects of the codon–anticodon interaction into consideration This view classifies the codons into ‘strong’, ‘weak’ and ‘intermediate’-strength based on the G/C versus A/U content of the first two codon positions into codons [4]. The C- and U-ending codons differ with respect to their interaction energy, necessitating mechanisms that regulate their translational efficiency [5]
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