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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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Cites
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Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
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“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
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InfluentialmRNA-based therapeutics: powerful and versatile tools to combat diseases
Qin, S., Tang, X., Chen, Y., Chen, K., Fan, N., Xiao, W., Zheng, Q., Li, G., Teng, Y., Wu, M., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01007-w · Cited by 852
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“Regions of increased rare codon frequency have been shown to decrease protein expression and mRNA stability (Presnyak et al., 2015; Weinberg et al., 2016).”
InfluentialSelf-citationThe dawn of mRNA vaccines: the COVID-19 case
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“49, 50 Additional sites within the mRNA construct are available for optimization as well.”
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Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations
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Upstream ORFs are prevalent translational repressors in vertebrates
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“Conversely, efficient translation of the protein-coding region has been implicated as a major factor in maintaining RNA stability (Huch & Nissan, 2014; Presnyak et al , 2015), so uORF regulation of steady-state RNA level could also arise as an effect of translational repression.”
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“The ability of tRNA modifications to increase the fidelity, accuracy and speed of translation of transcripts with distinct codon abundances ( codon optimality ) 252 can also be used to upregulate protein synthesis.”
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“Indeed, a recently emerging area is that codon optimality can influence mRNA stability by yet unknown mechanisms that depend on its translation (Presnyak et al., 2015).”
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Park, J. W., Lagniton, P. N. P., Liu, Y., & Xu, R.-H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.59233 · Cited by 321
“Moreover, the codon optimization is essential for the mRNA stability as the codon-dependent translation elongation rate has been implicated as a major determinant of the mRNA stability [67].”
BackgroundBazzini, A., Viso, F. D., Moreno-Mateos, M. A., Johnstone, T. G., Vejnar, C. E., Qin, Y., Yao, J., Khokha, M. K., & Giráldez, A. J. (2016) · The EMBO Journal · doi:10.15252/embj.201694699 · Cited by 309
“Comparison of the two methods revealed consistent effects for most codons on mRNA stability observed in the reporter library (rCSI) and the endogenous mRNAs (CSC) (Figs lF and EVlG) (zebrafish, P = le-3, R = 0.4, Spearman; Xenopus, P = 3e-3, R = 0.4, Spearman).”
InfluentialSynonymous mutations in representative yeast genes are mostly strongly non-neutral
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InfluentialJia, B., & Jeon, C. O. (2016) · Open Biology · doi:10.1098/rsob.160196 · Cited by 295
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InfluentialSelf-citationShort poly(A) tails are a conserved feature of highly expressed genes
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InfluentialSelf-citationRibosome Profiling: Global Views of TranslationPreprint
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BackgroundInfluentialTranslation affects mRNA stability in a codon-dependent manner in human cells
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BackgroundInfluentialCells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions
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“The OPT mRNA contains only optimal codons, while the NON-OPT mRNA bears only non-optimal codons; this distinction causes them to degradewith a 4-fold difference in half-life (Presnyak et al., 2015).”
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“Codon usage in yeast was recently implicated as the major determinant of mRNA stability, based upon a genome-wide analysis of mRNA stability which revealed a strong correlation between mRNA half-life and optimality of codons used to encode the gene (Figure 2) [39].”
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“As a result, the rate and efficiency of the protein translation are increased [14,23,40].”
BackgroundAdjacent Codons Act in Concert to Modulate Translation Efficiency in Yeast
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InfluentialThe ribosome in action: Tuning of translational efficiency and protein folding
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BackgroundInfluentialSelf-citationThe Dynamics of Cytoplasmic mRNA Metabolism
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P-body assembly requires DDX6 repression complexes rather than decay or Ataxin2/2L complexes
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“Recently Presnyak et al. (2015) showed in yeast that the presence of suboptimal codons leads to mRNA destabilization in addition to slow translational elongation.”
BackgroundTheoretical basis for stabilizing messenger RNA through secondary structure design
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Translational control of stem cell function
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“Furthermore, maximization of GC (guanine–cytosine) content in combination with codon optimization by selection of frequent codons in the coding region also allows to enhanced stability and translation [80,81].”
BackgroundThe Yin and Yang of codon usage
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A novel class of microRNA-recognition elements that function only within open reading frames
Zhang, K., Zhang, X., Cai, Z., Zhou, J., Cao, R., Zhao, Y., Chen, Z., Wang, D., Ruan, W., Zhao, Q. C., et al. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0136-3 · Cited by 172
Loughrey, D., & Dahlman, J. E. (2022) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00601 · Cited by 173
Direct epitranscriptomic regulation of mammalian translation initiation through N4-acetylcytidine
Arango, D., Sturgill, D. M., Yang, R., Kanai, T., Bauer, P., Roy, J., Wang, Z., Hosogane, M., Schiffers, S., & Oberdoerffer, S. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.05.016 · Cited by 175
Nanoscale platforms for messenger RNA delivery
Li, B., Zhang, X., & Dong, Y. (2019) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1530 · Cited by 170
“…of exogenous mRNA can be enhanced by a number of methods such as UTR manipulation, codon optimization, chemical modification, and elongation of poly(A) tail of mRNA (Grabbe et al., 2016; Loomis, Kirschman, Bhosle, Bellamkonda, & Santangelo, 2016; Presnyak et al., 2015; Yamamoto et al., 2009).”
Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts
Těšina, P., Lessen, L. N., Buschauer, R., Cheng, J., Wu, C. C., Berninghausen, O., Buskirk, A. R., Becker, T. A., Beckmann, R., & Green, R. (2019) · The EMBO Journal · doi:10.15252/embj.2019103365 · Cited by 166
Codon bias confers stability to human mRNAs
Hia, F., Yang, S. F., Shichino, Y., Yoshinaga, M., Murakawa, Y., Vandenbon, A., Fukao, A., Fujiwara, T., Landthaler, M., Natsume, T., et al. (2019) · EMBO Reports · doi:10.15252/embr.201948220 · Cited by 171
Operon mRNAs are organized into ORF-centric structures that predict translation efficiency
Burkhardt, D. H., Rouskin, S., Zhang, Y., Li, G., Weissman, J. S., & Gross, C. A. (2017) · eLife · doi:10.7554/elife.22037 · Cited by 166
“Additionally, there is evidence that codon usage correlates with mRNA halflife in both eukaryotes and prokaryotes (Boël et al., 2016; Presnyak et al., 2015).”
Stein, K. C., & Frydman, J. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.rev118.002814 · Cited by 169
“Indeed, codon optimality globally influences mRNA decay (99).”
BackgroundThe genetic and biochemical determinants of mRNA degradation rates in mammals
Agarwal, V., & Kelley, D. R. (2022) · Genome Biology · doi:10.1186/s13059-022-02811-x · Cited by 155
“Moreover, the signs of coefficients associated with codon frequencies are consistent with previously published human codon stability coefficients (CSCs) [26, 27, 29, 30], which were computed based upon an isolated Pearson or Spearman correlation between the codon frequencies and half-lives [28].”
MethodRibosome pausing, a dangerous necessity for co-translational events
Collart, M. A., & Weiss, B. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz763 · Cited by 157
“In 2015, the Coller laboratory published a study indicating that the overall codon composition of mRNAs, namely the relative percentage of codons above a certain threshold of optimality to the percentage of those below this threshold, correlates with mRNA half-life genome-wide (9).”
BackgroundThe human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA
Pinto, R., Vågbø, C. B., Jakobsson, M. E., Kim, Y., Baltissen, M. P. A., O’Donohue, M.-F., Guzmán, U. H., Małecki, J., Wu, J., Kirpekar, F., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1147 · Cited by 145
“on tRNA modifications and the modification of elongation factors, such as eEF1A, and affects protein homeostasis and mRNA turnover (37,41,57,77,78).”
BackgroundRibosome states signal RNA quality control
D’Orazio, K. N., & Green, R. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.02.022 · Cited by 147
“Meanwhile, if a ribosome is stuck on a poly-A tail, the cell does not recruit Cue2 or Xrn1, but instead the SKI complex is essential for both degradation and ribosome rescue (see Figure 3).”
BackgroundInfluentialThe regulation of protein translation and its implications for cancer
Song, P., Yang, F., Jin, H., & Wang, X. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00444-9 · Cited by 144
Insights into the mechanisms of eukaryotic translation gained with ribosome profiling
Andreev, D. E., O’Connor, P. B. F., Loughran, G., Dmitriev, S. E., Baranov, P. V., & Shatsky, I. N. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1190 · Cited by 151
“This may have significant implications, for example Presnyak et al. calculated the half-life of ADH1 to be 4.2 min and 31.7 min for polyA selected and rRNA depleted RNA, respectively (125).”
InfluentialTranslation of neutrally evolving peptides provides a basis for de novo gene evolution
Ruiz‐Orera, J., Verdaguer-Grau, P., Villanueva‐Cañas, J. L., Messeguer, X., & Albà, M. M. (2018) · Nature Ecology & Evolution · doi:10.1038/s41559-018-0506-6 · Cited by 138
Miller, D., Brandt, N., & Gresham, D. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007406 · Cited by 135
Structural and molecular mechanisms for the control of eukaryotic 5′–3′ mRNA decay
Mugridge, J. S., Coller, J., & Gross, J. D. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0164-z · Cited by 133
Self-citationZhang, H., Vandesompele, J., Braeckmans, K., Smedt, S. C. D., & Remaut, K. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00194f · Cited by 146
Codon optimality-mediated mRNA degradation: Linking translational elongation to mRNA stability
Bae, H., & Coller, J. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.03.032 · Cited by 135
Self-citationConnections Underlying Translation and mRNA Stability
Radhakrishnan, A., & Green, R. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.05.025 · Cited by 132
Inosine in Biology and Disease
Srinivasan, S., Torres, A. G., & de Pouplana, L. R. (2021) · Genes · doi:10.3390/genes12040600 · Cited by 130
“In yeast, the inosine-mediated synonymous codon changes do not result in protein recoding but they may affect the RNA stability and the translation efficiency, depending on tRNA availability and codon usage for the modified codon [122], and the same was identified in mouse oocytes [123,124].”
BackgroundCoding regions affect mRNA stability in human cells
Narula, A., Ellis, J., Taliaferro, J. M., & Rissland, O. S. (2019) · RNA · doi:10.1261/rna.073239.119 · Cited by 127
“Many differentORF features have been associated with mRNA stability: transcript or ORF length; local secondary structure; 3′UTR-like regulation; and codon usage (Schnall-Levin et al. 2011; Duan et al. 2013; Geisberg et al. 2014; Presnyak et al. 2015; Neymotin et al. 2016).”
BackgroundMethodResultInfluentialThe cryo-EM structure of a ribosome–Ski2-Ski3-Ski8 helicase complex
Schmidt, C. M., Kowalinski, E., Shanmuganathan, V., Defenouillère, Q., Braunger, K., Heuer, A., Pech, M., Namane, A., Berninghausen, O., Fromont‐Racine, M., et al. (2016) · Science · doi:10.1126/science.aaf7520 · Cited by 124
SARS-CoV-2 (Covid-19) vaccines structure, mechanisms and effectiveness: A review
Fathizadeh, H., Afshar, S., Masoudi, M. R., Gholizadeh, P., Asgharzadeh, M., Ganbarov, K., Köse, Ş., Yousefi, M., & Kafil, H. S. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.08.076 · Cited by 126
Disome-seq reveals widespread ribosome collisions that promote cotranslational protein folding
Zhao, T., Chen, Y., Li, Y., Wang, J., Chen, S., Gao, N., & Qian, W. (2021) · Genome biology · doi:10.1186/s13059-020-02256-0 · Cited by 125
“Synonymous codons are known to be recognized at variable rates [19, 20, 53], which further regulate mRNA stability [31, 59]; however, the impact of codon optimality on”
BackgroundSelf-citationDifferences in codon bias and GC content contribute to the balanced expression of TLR7 and TLR9
Newman, Z. R., Young, J. M., Ingolia, N. T., & Barton, G. M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518976113 · Cited by 118
Zhao, F., Yu, C.-H., & Liu, Y. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx501 · Cited by 120
Barahimipour, R., Strenkert, D., Neupert, J., Schroda, M., Merchant, S., & Bock, R. (2015) · The Plant Journal · doi:10.1111/tpj.13033 · Cited by 117
“This conclusion is in line with recent findings that, in budding yeast, mRNA stability is strongly influenced by codon usage and, hence, translation rates (Presnyak et al., 2015).”
BackgroundResultCodon and amino acid content are associated with mRNA stability in mammalian cells
Forrest, M. E., Pinkard, O., Martin, S., Sweet, T. J., Hanson, G., & Coller, J. (2020) · PLOS ONE · doi:10.1371/journal.pone.0228730 · Cited by 116
Self-citationFrom structural design to delivery: mRNA therapeutics for cancer immunotherapy
Zhou, F., Huang, L., Li, S., Yang, W., Chen, F., Cai, Z., Liu, X., Xu, W., Lehto, V., Lächelt, U., et al. (2023) · Exploration · doi:10.1002/exp.20210146 · Cited by 117
Chen, F., Wu, P., Deng, S., Zhang, H., Hou, Y., Hu, Z., Zhang, J., Chen, X., & Yang, J. (2020) · Nature Ecology & Evolution · doi:10.1038/s41559-020-1124-7 · Cited by 112
Translation and mRNA Stability Control
Wu, Q., & Bazzini, A. (2023) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052621-091808 · Cited by 120
The Maternal-to-Zygotic Transition During Vertebrate Development
Yartseva, V., & Giráldez, A. J. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2015.07.020 · Cited by 112
Systemic delivery of mRNA and DNA to the lung using polymer-lipid nanoparticles
Kaczmarek, J. C., Patel, A. K., Rhym, L. H., Palmiero, U. C., Bhat, B., Heartlein, M. W., DeRosa, F., & Anderson, D. G. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.120966 · Cited by 110
Codon usage influences fitness through RNA toxicity
Mittal, P., Brindle, J., Stephen, J. O., Plotkin, J. B., & Kudla, G. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810022115 · Cited by 100
Phosphorylation of the Ribosomal Protein RPL12/uL11 Affects Translation during Mitosis
Imami, K., Milek, M., Bogdanow, B., Yasuda, T., Kastelić, N., Zauber, H., Ishihama, Y., Landthaler, M., & Selbach, M. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.019 · Cited by 120
“It is tempting to speculate that phosphorylated RPL12/uL11 modulates the binding affinity toward specific tRNAs, facilitating elongation of specific mRNAs (Presnyak et al., 2015).”
BackgroundMethodInfluentialVariation and selection on codon usage bias across an entire subphylum
LaBella, A. L., Opulente, D. A., Steenwyk, J. L., Hittinger, C. T., & Rokas, A. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008304 · Cited by 106
Codon Usage and Splicing Jointly Influence mRNA Localization
Mordstein, C., Savisaar, R., Young, R. S., Bazile, J., Talmane, L., Luft, J., Liss, M. A., Taylor, M. S., Hurst, L. D., & Kudla, G. (2020) · Cell Systems · doi:10.1016/j.cels.2020.03.001 · Cited by 102
“Recent studies highlight patterns of codon usage as major determinants of RNA stability in yeast (Presnyak et al., 2015), zebrafish (Mishima and Tomari, 2016), and other species (Bazzini et al., 2016).”
Background
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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