Cited by 1,078RNA and protein synthesis mechanismsRNA Research and SplicingRNA modifications and cancer

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Codon Optimality Is a Major Determinant of mRNA Stability

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Presnyak, Vladimir, Alhusaini, Najwa, Chen, Ying-Hsin, Martin, Sophie, Morris, Nathan, Kline, Nicholas, Olson, Sara, Weinberg, David, Baker, Kristian E., Graveley, Brenton R., Coller, Jeff·2015·Cell

DOI 10.1016/j.cell.2015.02.029PMC PMC4359748

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Abstract

mRNA degradation represents a critical regulated step in gene expression. Although the major pathways in turnover have been identified, accounting for disparate half-lives has been elusive. We show that codon optimality is one feature that contributes greatly to mRNA stability. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched in codons designated optimal, whereas unstable mRNAs contain predominately non-optimal codons. Substitution of optimal codons with synonymous, non-optimal codons results in dramatic mRNA destabilization, whereas the converse substitution significantly increases stability. Further, we demonstrate that codon optimality impacts ribosome translocation, connecting the processes of translation elongation and decay through codon optimality. Finally, we show that optimal codon content accounts for the similar stabilities observed in mRNAs encoding proteins with coordinated physiological function. This work demonstrates that codon optimization exists as a mechanism to finely tune levels of mRNAs and, ultimately, proteins.

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“The overall result is not surprising, as codon bias has been well studied (Gustafsson et al., 2004); however, the pattern of codon usage demonstrates that certain classes of mRNAs predominately use either optimal or non-optimal codons (Figures 3A and 3B; overrepresented codons in yellow,…”
Background
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“A significant increase of yeast mRNA halflife is detected when non-optimal codons are converted to optimal codons in a manner minimizing changes in the GC content and the predicted RNA secondary structure (92).”
Background
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Background
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“Previous work from our labs and others have demonstrated the correlation between codon optimality and mRNA decay rates (Presnyak et al. 2015; Boёl et al. 2016; Harigaya and Parker 2016; Mishima and Tomari 2016; Bazzini et al. 2016).”
BackgroundResultSelf-citation
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“Codon usage and optimality have been a subject of immense interest, given their role in regulating many molecular processes such as mRNA stability and decay(39, 40), ribosome decoding fidelity(41), and mRNA translation efficiency(5, 42).”
Background
Dissecting translation elongation dynamics through ultra-long tracking of single ribosomesPreprint
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“Codons i with cTE i values of 0.47 or higher are categorized as optimal, whereas those with lower values are deemed nonoptimal [60].”
Influential
Unconventional codon usage bias mediates mRNA translational dynamics in macrophages
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“In contrast, in all other mouse tissues analyzed in this study, the high-abundance mRNAs were biased toward GC3 codons. mRNA stability is affected by codon usage via regulation of the translation elongation rate [48,49].”
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“Codon usage optimization — de ﬁ ned as the preferential employment of synonymous codons to improve translational ﬁ delity and effectiveness — is a recognized phenomenon in both unicellular and multicellular organisms (Presnyak et al., 2015; Sen et al., 2020).”
Nuclear effects play an important role in determining codon usage-dependent human gene expression
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Codon Clarity or Conundrum?
Aalberts, D. P., Boël, G., & Hunt, J. F. (2017) · Cell Systems · doi:10.1016/j.cels.2017.01.004 · Cited by 4
“This study echoed other recent studies showing similar correlations between codon usage and mRNA decay rates in the yeast Saccharomyces cerevisiae (Presnyak et al, 2015) and the zebrafish Danio rerio.”
BackgroundResult
Destabilization of Eukaryote mRNAs by 5′ Proximal Stop Codons Can Occur Independently of the Nonsense-Mediated mRNA Decay Pathway
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Authors: Presnyak, V., Alhusaini, N., Chen, Y.-H., Martin, S., Morris, N., Kline, N., Olson, S., Weinberg, D., Baker, K. E., Graveley, B. R., & Coller, J.
Affiliations: Case Western Reserve University (US)
UConn Health (US)
University of California, San Francisco (US)
Corresponding author: Coller, Jeff
ORCID: Presnyak, Vladimir
Alhusaini, Najwa
Martin, Sophie
Morris, Nathan
Kline, Nicholas
Olson, Sara
Weinberg, David
Baker, Kristian E.
Graveley, Brenton R.
Coller, Jeff
Venue: Cell
Publisher: Elsevier BV
Published: 2015-03
Volume: 160
Issue: 6
Pages: 1111-1124
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2015.02.029
PMC: PMC4359748
OpenAlex: W2013321787
Cited by: 1,078
References: 43
Citations by year: 2026: 94 · 2025: 139 · 2024: 122 · 2023: 115 · 2022: 77 · 2021: 127 · 2020: 93 · 2019: 70 · 2018: 96 · 2017: 68 · 2016: 57 · 2015: 20
FWCI: 34.90
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 377 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (GM080465, GM095621)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords: codon optimality, mRNA stability, mRNA degradation, codon usage bias, synonymous codons, ribosome translocation, translation elongation, gene expression regulation, mRNA half-life
MeSH terms: Codon, RNA, Fungal, RNA, Messenger, Saccharomyces cerevisiae, Protein Biosynthesis, RNA Stability

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Codon Optimality Is a Major Determinant of mRNA Stability

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