Synonymous codons, ribosome speed, and eukaryotic gene expression regulation

Tarrant, Daniel; Haar, Tobias von der

doi:10.1007/s00018-014-1684-2

Cited by 35 publications

(37 citation statements)

References 108 publications

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“…These pauses are lost upon the addition of CHX, both for 5PSeq and ribosome profiling (Figures 5C and S5A), suggesting that the generalized translational inhibition caused by CHX is sufficient to mask naturally occurring ribosome pausing sites. This is consistent with ribosomal pausing having been difficult to detect by ribosome profiling (Tarrant and von der Haar, 2014). Additionally, the pausing observed for CGA and CCG codons in normal conditions (Figure 4A) is lost upon oxidative stress (Figure 5B).…”

Section: Resultssupporting

confidence: 80%

Widespread Co-translational RNA Decay Reveals Ribosome Dynamics

Pelechano

Steinmetz

2015

Cell

261

360

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Summary It is generally assumed that mRNAs undergoing translation are protected from decay. Here we show that mRNAs are in fact co-translationally degraded. This is a widespread and conserved process affecting most genes, where 5’-3’ transcript degradation follows the last translating ribosome, producing an in vivo ribosomal footprint. By sequencing the ends of 5’phosphorylated mRNA degradation intermediates, we obtain a genome-wide drug-free measurement of ribosome dynamics. We identify general translation termination pauses in both normal and stress conditions. In addition, we describe novel codon-specific ribosomal pausing sites in response to oxidative stress, which are dependent on the RNase Rny1. Our approach is simple and straightforward, and does not require the use of translational inhibitors or in vitro RNA footprinting that can alter ribosome protection patterns.

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Section: Resultssupporting

confidence: 80%

Widespread Co-translational RNA Decay Reveals Ribosome Dynamics

Pelechano

Steinmetz

2015

Cell

261

360

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“…Such phenomena were previously only observed in metazoans (Stadler and Fire, 2011). This observation is consistent with the expectation that wobble pairing is likely to be delayed by the higher probability of tRNA rejection (Tarrant and von der Haar, 2014). Our result therefore provides evidence for the first time in yeast to support such a mechanism.…”

Section: Contributionssupporting

confidence: 92%

“…According to the Wobble hypothesis (Crick, 1966), the last two bases of the tRNA anticodon form Watson-Crick base pairs and bond strongly to the first two bases of the codon. However, the anticodon's first base can form a wobble pair: the base G can either Watson-Crick pair with C or wobble pair with U; the base I (inosine, edited from A) can also both wobble pair with C and U, but I:U pairing has a less favorable geometry (Stadler and Fire, 2011); the base U can Watson-Crick pair with A and wobble pair with G. It has been hypothesized that wobble-paired codons tend to be translated slower than their synonymous Watson-Crick paired codons, since wobble pairs are more likely to be rejected before peptidyl transfer, causing the tRNA selection cycle to be repeated (Tarrant and von der Haar, 2014).…”

Section: Wobble-pairing Codons Translate Slower Than Watson-crick Paimentioning

confidence: 99%

“…We expect the decoding time difference between two wobble-paired codons to be smaller than the difference between a wobble-pair codon and a Watson-Crick pair codon, if the wobble-paired tRNA is truly more likely to leave the ribosome without successful peptidyl transfer (Tarrant and von der Haar, 2014). For the three codon pairs being compared, we would therefore expect the time difference between I:C and I:U to be smaller than the time difference between G:C and G:U, and between U:A and U:G. To control for the absolute level of the translation time, we use the relative decoding time difference between a synonymous codon pair.…”

Section: Wobble-pairing Codons Translate Slower Than Watson-crick Paimentioning

confidence: 99%

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Accurate Recovery of Ribosome Positions Reveals Slow Translation of Wobble-Pairing Codons in Yeast

Wang

McManus

Kingsford

2016

Lecture Notes in Computer Science

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Ribosome profiling quantitatively captures ribosome locations during translation. The resulting profiles of ribosome locations are widely used to study translational speed. However, an accurate estimation of the ribosome location depends on identifying the A-site from ribosome profiling reads, a problem that was previously unsolved. Here, we propose a novel method to estimate the ribosome A-site positions from high-coverage ribosome profiling reads. Our model allows more reads to be used, accurately explains the 3-nt periodicity of ribosome profiling reads from various lengths, and recovers consistent ribosome positions across different lengths. Our recovered ribosome positions are correctly highly skewed toward a single frame within a codon. They retain subcodon resolution and enable detection of off-frame translational events, such as frameshifts. Our method improves the correlation with other estimates of codon decoding time. Furthermore, the refined profiles show that yeast wobble-pairing codons are translated slower than their synonymous Watson-Crick-pairing codons. These results provide evidence that protein synthetic rate can be tuned by codon usage bias.

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“…Furthermore, a recent study using meticulous measurement of translation velocities on Neurospora mRNAs showed clearly that non-optimal codons significantly slow translation, while abundant codon stretches are rapidly translated (27). Supporting a regulatory role for rare codons, modelling of translation suggests that there are sub-populations of mRNAs whose translation are elongation-regulated (28,29), in which codons translated by low-abundance tRNAs play a regulatory role. These predictions were experimentally validated on artificial mRNAs by controlling the rate of initiation on reporters engineered to contain multiple rare codons (30).…”

Section: Introductionmentioning

confidence: 99%

Identification of the mRNA targets of tRNA-specific regulation using genome-wide simulation of translation

Gorgoni¹,

Ciandrini²,

McFarland³

et al. 2016

Nucleic Acids Res

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tRNA gene copy number is a primary determinant of tRNA abundance and therefore the rate at which each tRNA delivers amino acids to the ribosome during translation. Low-abundance tRNAs decode rare codons slowly, but it is unclear which genes might be subject to tRNA-mediated regulation of expression. Here, those mRNA targets were identified via global simulation of translation. In-silico mRNA translation rates were compared for each mRNA in both wild-type and a \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${\rm{tRNA}}_{{\rm{CUG}}}^{{\rm{Gln}}}$\end{document} sup70-65 mutant, which exhibits a pseudohyphal growth phenotype and a 75% slower CAG codon translation rate. Of 4900 CAG-containing mRNAs, 300 showed significantly reduced in silico translation rates in a simulated tRNA mutant. Quantitative immunoassay confirmed that the reduced translation rates of sensitive mRNAs were \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${\rm{tRNA}}_{{\rm{CUG}}}^{{\rm{Gln}}}$\end{document} concentration-dependent. Translation simulations showed that reduced \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${\rm{tRNA}}_{{\rm{CUG}}}^{{\rm{Gln}}}$\end{document} concentrations triggered ribosome queues, which dissipated at reduced translation initiation rates. To validate this prediction experimentally, constitutive gcn2 kinase mutants were used to reduce in vivo translation initiation rates. This repaired the relative translational rate defect of target mRNAs in the sup70-65 background, and ameliorated sup70-65 pseudohyphal growth phenotypes. We thus validate global simulation of translation as a new tool to identify mRNA targets of tRNA-specific gene regulation.

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Synonymous codons, ribosome speed, and eukaryotic gene expression regulation

Cited by 35 publications

References 108 publications

Widespread Co-translational RNA Decay Reveals Ribosome Dynamics

Widespread Co-translational RNA Decay Reveals Ribosome Dynamics

Accurate Recovery of Ribosome Positions Reveals Slow Translation of Wobble-Pairing Codons in Yeast

Identification of the mRNA targets of tRNA-specific regulation using genome-wide simulation of translation

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