Balanced Codon Usage Optimizes Eukaryotic Translational Efficiency

Qian, Wenfeng; Yang, Jian; Pearson, Nathaniel M.; Maclean, Calum J.; Zhang, Jianzhi

doi:10.1371/journal.pgen.1002603

Cited by 277 publications

(354 citation statements)

References 75 publications

(122 reference statements)

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“…This calculation quantifies the expectation that tRNAs expressed at lower abundances or that involve non-standard base pairing in their codon-anticodon interaction should require longer to translate. Consistent with previous reports [13,23,31,32], all CHX experiments report weak experiments from many different studies in yeast, grouped by hierarchical clustering. Red indicates positive correlation and blue indicates negative correlation.…”

Section: Pretreatment With Cycloheximide Consistently Changes Enrichmsupporting

confidence: 89%

Understanding biases in ribosome profiling experiments reveals signatures of translation dynamics in yeast

Hussmann

Patchett

Johnson

et al. 2015

Preprint

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Ribosome profiling produces snapshots of the locations of actively translating ribosomes on messenger RNAs. These snapshots can be used to make inferences about translation dynamics. Recent ribosome profiling studies in yeast, however, have reached contradictory conclusions regarding the average translation rate of each codon. Some experiments have used cycloheximide (CHX) to stabilize ribosomes before measuring their positions, and these studies all counterintuitively report a weak negative correlation between the translation rate of a codon and the abundance of its cognate tRNA. In contrast, some experiments performed without CHX report strong positive correlations. To explain this contradiction, we identify unexpected patterns in ribosome density downstream of each type of codon in experiments that use CHX. These patterns are evidence that elongation continues to occur in the presence of CHX but with dramatically altered codon-specific elongation rates. The measured positions of ribosomes in these experiments therefore do not reflect the amounts of time ribosomes spend at each position in vivo. These results suggest that conclusions from experiments in yeast using CHX may need reexamination. In particular, we show that in all such experiments, codons decoded by less abundant tRNAs were in fact being translated more slowly before the addition of CHX disrupted these dynamics. Author SummaryRibosome profiling measures the precise locations of millions of actively translating ribosomes on mRNAs. In theory, the frequency with which ribosomes are observed positioned over each type of codon can be used to quantify the speed with which each codon is translated. In practice, ribosome profiling experiments in yeast that use translation inhibitors to arrest translation before measuring the positions of ribosomes report very different Data Availability Statement: Sequencing data has been deposited to the SRA with accession number SRP060588.Funding: This work was supported by NIH grant R01-GM-093086 to SS and NIH grant GM053655 to AJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: The authors have declared that no competing interests exist.apparent translation speeds for each codon than experiments that do not use inhibitors.To explain this inconsistency, we show that a previously unappreciated mechanism causes experiments using translation inhibitors to not measure ribosomes at each position on mRNAs in proportion to the actual amount of time spent there in vivo. Understanding this mechanism reveals that experiments without inhibitors more accurately measure translation dynamics and provides guidance for the design and interpretation of future ribosome profiling experiments.

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Section: Pretreatment With Cycloheximide Consistently Changes Enrichmsupporting

confidence: 89%

Understanding biases in ribosome profiling experiments reveals signatures of translation dynamics in yeast

Hussmann

Patchett

Johnson

et al. 2015

Preprint

View full text Add to dashboard Cite

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“…For instance, the tRNA pool in mammals appears to be equally efficient at translating any transcriptome, regardless of cell type or condition (Rudolph et al 2016). While some works have suggested that preferentially used codons are not translated faster than unpreferred ones or that rare codons do not correlate with ribosome pausing (Qian et al 2012;Guo et al 2010;Pop et al 2014), other reports have suggested that differences in tRNA population are associated with diverse effects on translation (Lampson et al 2013;Goodarzi et al 2016). This is the case of a mutation of a tissue-specific tRNA expressed in the mouse nervous system, which led to ribosome stalling and that was implicated as the cause of neurodegeneration (Ishimura et al 2014).…”

Section: Translation Kineticsmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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“…Cellular fitness can also be affected by codon-tRNA balance [69]. Gingold et al [70] investigated this notion and revealed that the levels of endogenous tRNAs adapt to match the codon usage of mRNAs specifically expressed in differentiated versus proliferating cells.…”

Section: Pr Ospects and Overviewsmentioning

confidence: 99%

tRNA biology in the omics era: Stress signalling dynamics and cancer progression

Orioli

2016

BioEssays

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Recent years have seen a burst in the number of studies investigating tRNA biology. With the transition from a gene‐centred to a genome‐centred perspective, tRNAs and other RNA polymerase III transcripts surfaced as active regulators of normal cell physiology and disease. Novel strategies removing some of the hurdles that prevent quantitative tRNA profiling revealed that the differential exploitation of the tRNA pool critically affects the ability of the cell to balance protein homeostasis during normal and stress conditions. Furthermore, growing evidence indicates that the adaptation of tRNA synthesis to cellular dynamics can influence translation and mRNA stability to drive carcinogenesis and other pathological disorders. This review explores the contribution given by genomics, transcriptomics and epitranscriptomics to the discovery of emerging tRNA functions, and gives insights into some of the technical challenges that still limit our understanding of the RNA polymerase III transcriptional machinery.

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Balanced Codon Usage Optimizes Eukaryotic Translational Efficiency

Cited by 277 publications

References 75 publications

Understanding biases in ribosome profiling experiments reveals signatures of translation dynamics in yeast

Understanding biases in ribosome profiling experiments reveals signatures of translation dynamics in yeast

Protein folding and tRNA biology

tRNA biology in the omics era: Stress signalling dynamics and cancer progression

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