Codon influence on protein expression in E. coli correlates with mRNA levels

Boël, Grégory; Letso, Reka R.; Neely, H.; Price, W. Nicholson; Wong, Kam Ho; Su, Min; Luff, Jon D.; Valecha, Mayank; Everett, J.K.; Acton, Thomas; Xiao, Rong; Montelione, Gaetano T.; Aalberts, Daniel P.; Hunt, J.F.

doi:10.1038/nature16509

Cited by 378 publications

(396 citation statements)

References 62 publications

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“…Codon usage, which affects the translation elongation rate, also regulates mRNA stability (Hoekema et al 1987;Presnyak et al 2015;Bazzini et al 2016;Mishima and Tomari 2016). Further correlations between codon usage and mRNA stability have been reported in E. coli and S. pombe (Boël et al 2016;Harigaya and Parker 2016). Adjacent codon pairs were also demonstrated to associate with mRNA decay in addition to individual codons in S. cerevisiae (Harigaya and Parker 2017).…”

Section: Introductionmentioning

confidence: 90%

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Cheng

Maier

Avsec

et al. 2017

RNA

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The stability of mRNA is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for Saccharomyces cerevisiae based on functional mRNA sequence features that explains 59% of the half-life variation between genes and predicts half-life at a median relative error of 30%. The model revealed a new destabilizing 3 ′ ′ ′ ′ ′ UTR motif, ATATTC, which we functionally validated. Codon usage proves to be the major determinant of mRNA stability. Nonetheless, single-nucleotide variations have the largest effect when occurring on 3 ′ ′ ′ ′ ′ UTR motifs or upstream AUGs. Analyzing mRNA half-life data of 34 knockout strains showed that the effect of codon usage not only requires functional decapping and deadenylation, but also the 5 ′ ′ ′ ′ ′ -to-3 ′ ′ ′ ′ ′ exonuclease Xrn1, the nonsense-mediated decay genes, but not no-go decay. Altogether, this study quantitatively delineates the contributions of mRNA sequence features on stability in yeast, reveals their functional dependencies on degradation pathways, and allows accurate prediction of half-life from mRNA sequence.

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Section: Introductionmentioning

confidence: 90%

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Cheng

Maier

Avsec

et al. 2017

RNA

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“…The dwelling time of a ribosome on a specific codon depends primarily on the abundance of the corresponding tRNA [5,6]. Understanding how codon sequences determine protein production rates can potentially unlock many synthetic applications [7,8].…”

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confidence: 99%

Deciphering mRNA Sequence Determinants of Protein Production Rate

2018

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One of the greatest challenges in biophysical models of translation is to identify coding sequence features that affect the rate of translation and therefore the overall protein production in the cell. We propose an analytic method to solve a translation model based on the inhomogeneous totally asymmetric simple exclusion process, which allows us to unveil simple design principles of nucleotide sequences determining protein production rates. Our solution shows an excellent agreement when compared to numerical genome-wide simulations of S. cerevisiae transcript sequences and predicts that the first 10 codons, which is the ribosome footprint length on the mRNA, together with the value of the initiation rate, are the main determinants of protein production rate under physiological conditions. Finally, we interpret the obtained analytic results based on the evolutionary role of the codons' choice for regulating translation rates and ribosome densities.

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“…We wondered if the translating ribosome might transition from a translation initiation mode through the N terminus, which is strongly influenced by the presence of rare codons, codon context, mRNA secondary structure, tRNA modifications, and other translation factors, into a more robust translation machine that is less affected by these factors. Recently, Boël et al determined that the codon choice in the initial 20 codons of Escherichia coli transcripts correlated with translation efficiency and mRNA stability (14).…”

Section: Isolation Of Synonymous Suppressor Mutations Of Pro8 Ccgmentioning

confidence: 99%

Case for the genetic code as a triplet of triplets

Chevance

Hughes

2017

Proc. Natl. Acad. Sci. U.S.A.

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The efficiency of codon translation in vivo is controlled by many factors, including codon context. At a site early in the Salmonella flgM gene, the effects on translation of replacing codons Thr6 and Pro8 of flgM with synonymous alternates produced a 600-fold range in FlgM activity. Synonymous changes at Thr6 and Leu9 resulted in a twofold range in FlgM activity. The level of FlgM activity produced by any codon arrangement was directly proportional to the degree of in vivo ribosome stalling at synonymous codons. Synonymous codon suppressors that corrected the effect of a translation-defective synonymous flgM allele were restricted to two codons flanking the translation-defective codon. The various codon arrangements had no apparent effects on flgM mRNA stability or predicted mRNA secondary structures. Our data suggest that efficient mRNA translation is determined by a triplet-of-triplet genetic code. That is, the efficiency of translating a particular codon is influenced by the nature of the immediately adjacent flanking codons. A model explains these codon-context effects by suggesting that codon recognition by elongation factor-bound aminoacyl-tRNA is initiated by hydrogen bond interactions between the first two nucleotides of the codon and anticodon and then is stabilized by base-stacking energy over three successive codons.translation | genetic code | context effects on translation | tRNA | synonymous codon effects T he DNA sequence is transcribed to form mRNA, which then is translated into protein by ribosomes. The genetic code consists of 64 triplet RNA codons that specify the 20 amino acids and sites of translation termination (stop codons). The decoding process involves interaction between a specific codon in the mRNA and the three-base anticodon of the cognate aminoacyltRNA (bases 36, 35, and 34 within the anticodon loop) (1). The code is redundant, in that many amino acids are specified by two or more triplet sequences. In addition, codons specifying a particular amino acid are recognized by single or multiple tRNAs. Most tRNA species recognize codons that differ in the third or "wobble" position. Modifications of tRNA bases also contribute to tRNA recognition of single or multiple anticodons as the tRNA enters the ribosome at the A site (1). Codons are read in the 5′-3′ direction of the mRNA by sequential interactions with tRNA aligned 3′-5′ vis-à-vis each codon. Stacking-related wobble codon recognition is mediated by extensive modification of position 34 of the tRNA codon.Other base modifications stabilize the interaction of the tRNA with ribosomal A site, i.e., methylation of a G at position 37 prevents tRNA slippage, which would result in a shift in the translation reading frame (1). Fig. S1 illustrates the initial translation steps starting with codon recognition and proceeding to peptidyl transfer. GTP-bound elongation factor Tu (EF-Tu) brings aminoacyl-tRNA to the A site of the ribosome. WatsonCrick pairing at the first two bases of the codon initiates EF-TutRNA docking followed by triplet sta...

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Codon influence on protein expression in E. coli correlates with mRNA levels

Cited by 378 publications

References 62 publications

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Deciphering mRNA Sequence Determinants of Protein Production Rate

Case for the genetic code as a triplet of triplets

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