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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Previous strategies to increase mRNA stability have yielded modest improvements in RNA stability.
“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]
The Results section reports that reporters with optimal codons were about fourfold more stable than those with non-optimal codons, supporting an improvement in mRNA stability. The paper does not characterize that improvement as modest or establish that previous stabilization strategies generally yielded only modest gains. (LLM, conf=0.79)
Experimental — accuracy not yet measuredCodon modification is critical for mRNA stability.
“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
Researchers usually performed codon optimization on the antigen-coding sequence to enhance translation efficiency.
“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]
Codon optimization in the mRNA sequence, for example to match host tRNA abundances or as a determinant of secondary structures, can drastically impact protein synthesis rate and ribosome dwell time.
“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]
The rate of codon-dependent translation elongation is a primary factor of mRNA stability.
“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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- 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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