The DOI matches its Crossref record; 41 of the 43 references it cites were found in a registry or an index.
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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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
In the citing paper
“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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Citations
Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · cited 2×
“Alignment and Half-Life Calculation Reads were aligned to the S. cerevisiae reference genome using bowtie (Langmead et al., 2009), with the unaligned reads then aligned to the sequences of the controls in the same way.”
MethodTrapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556
Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling
Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S., & Weissman, J. S. (2009) · Science · doi:10.1126/science.1168978 · Cited by 3,853 · cited 1×
“Several ribosomal profiling studies have failed to detect codon-specific differences in the translation of optimal and non-optimal codons (Ingolia et al., 2009; Qian et al., 2012; Charneski and Hurst, 2013).”
BackgroundOpen source clustering software
de Hoon, M., Imoto, S., Nolan, J., & Miyano, S. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth078 · Cited by 3,047
Java Treeview—extensible visualization of microarray data
Saldanha, A. J. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth349 · Cited by 2,991
Gietz, R. D., & Sugino, A. (1988) · Gene · doi:10.1016/0378-1119(88)90185-0 · Cited by 2,851
Codon bias and heterologous protein expression
Gustafsson, C., Govindarajan, S., & Minshull, J. (2004) · Trends in Biotechnology · doi:10.1016/j.tibtech.2004.04.006 · Cited by 1,330 · cited 2×
“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,…”
BackgroundMistranslation-Induced Protein Misfolding as a Dominant Constraint on Coding-Sequence Evolution
Drummond, D. A., & Wilke, C. O. (2008) · Cell · doi:10.1016/j.cell.2008.05.042 · Cited by 1,065 · cited 2×
“Critically, optimal codons are postulated to be decoded faster and more accurately by the ribosome than non-optimal codons (Akashi, 1994; Drummond and Wilke, 2008), which are hypothesized to slow translation elongation (Novoa and Ribas de Pouplana, 2012; Tuller et al., 2010).”
BackgroundAn evolutionarily conserved mechanism for controlling the efficiency of protein translation
Tuller, T., Carmi, A., Vestsigian, K., Navon, S., Dorfan, Y., Zaborske, J., Pan, T., Dahan, O., Furman, I., & Pilpel, Y. (2010) · Cell · doi:10.1016/j.cell.2010.03.031 · Cited by 874 · cited 1×
“Critically, optimal codons are postulated to be decoded faster and more accurately by the ribosome than non-optimal codons (Akashi, 1994; Drummond and Wilke, 2008), which are hypothesized to slow translation elongation (Novoa and Ribas de Pouplana, 2012; Tuller et al., 2010).”
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Cited by
Sorted by citations
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.012 · Cited by 1,127
“The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels.(5,6) Modification of the 50 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistan…”
Emerging issues in AAV-mediated in vivo gene therapy
Colella, P., Ronzitti, G., & Mingozzi, F. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2017.11.007 · Cited by 881
Engineering circular RNA for potent and stable translation in eukaryotic cells
Wesselhoeft, R. A., Kowalski, P. S., & Anderson, D. G. (2018) · Nature Communications · doi:10.1038/s41467-018-05096-6 · Cited by 853
Codon optimality, bias and usage in translation and mRNA decay
Hanson, G., & Coller, J. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.91 · Cited by 825
Self-citationThe Stress Granule Transcriptome Reveals Principles of mRNA Accumulation in Stress Granules
Khong, A., Matheny, T., Jain, S., Mitchell, S. F., Wheeler, J. R., & Parker, R. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.10.015 · Cited by 787
“Codon Optimality: The fraction of the optimal codon for each gene was calculated using a custom script based on codon stabilization coefficients presented in a previous report (Presnyak et al., 2016).”
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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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