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Codon Optimality Is a Major Determinant of mRNA Stability
Open accessAbstract
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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“These strategies have yielded modest improvements in RNA stability10, 13–16, and thus alternative approaches to RNA stabilization, such as circularization, are desirable.”
From Engineering circular RNA for potent and stable translation in eukaryotic cells (2018) · cites this paper as [15]
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“Furthermore, the rate of codon-dependent translation elongation has been a primary factor of mRNA stability, codon modification is critical for mRNA stability (Presnyak et al. 2015).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Presnyak et al. 2015
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“Furthermore, the rate of codon-dependent translation elongation has been a primary factor of mRNA stability, codon modification is critical for mRNA stability (Presnyak et al. 2015).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Presnyak et al. 2015
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“To improve the safety, efficacy, and stability of mRNA vaccines, researchers usually performed codon optimization172,239–243 on the antigen-coding sequence to enhance translation efficiency.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [240]
In the citing paper
“Codon optimization in the mRNA sequence to e.g., match host transfer (t)RNA abundances, or as a determinant of introducing secondary structures, can drastically impact the protein synthesis rate and ribosome dwell time (i.e. mRNA functional half-life) [33,34]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [33]
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BackgroundSynonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
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“protein folding,(64) and codon usage also impacts mRNA stability.(90) For tightly regulated proteins, codon optimization may alter the safety and efficacy of protein expression;(63) selection of a codon-optimized cDNA should therefore be closely evaluated when designing a gene therapy vector.”
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mRNA Vaccines: Current Applications and Future Directions
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BackgroundNascent MSKIK peptide cancels ribosomal stalling by arrest peptides in Escherichia coli
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“increasingly clear, at least in yeast, in recent years.(56,57) It is also possible that the reduced eIF3m level causes mostly a general effect on translation of all mRNAs in the cells, which is not specific to particular mRNAs (except for the discussed genes).”
BackgroundCodon Harmonization of a Kir3.1-KirBac1.3 Chimera for Structural Study Optimization
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“It has previously been shown that codon usage plays a role in steady-state mRNA concentration, and that substitution of rare codons into a coding sequence negatively impacts mRNA stability [69,70].”
BackgroundΦX174 Attenuation by Whole-Genome Codon Deoptimization
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Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells
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“The preference for different codons has significant effects on mRNA stability (Presnyak et al., 2015), translation efficiency and accuracy (Gingold and Pilpel, 2011), and protein folding (Zhang et al.”
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“Synonymous changes are known to affect RNA transcript stability as well as translational efficiency, because of tRNA availability and codon usage [63,64].”
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“36,37 Despite the differences in protein expression levels, the ranking of expression intensity for the three BCDs remained consistent across all three proteins, with HP-7 showing the highest expression intensity, followed by HP-12 and then HP-6.”
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“First, a subset of ‘‘optimal’’ codons occur at a higher frequency in highly expressed genes (Gustafsson et al., 2004) and ‘‘nonoptimal’’ codons lead to increased ribosomal pausing and decreased mRNA half-life (Presnyak et al., 2015; Weinberg et al., 2016).”
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“Similarly, it has been established that mRNA half-lives are generally correlated with codon usage (65) and that even faster mRNA decay is associated with ICPs (66); we found that the mean, and median mRNA half-life of genes with ICPcons were reduced, compared to that of the other gene sets (Table 1).”
Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 160
- Issue
- 6
- Pages
- 1111-1124
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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