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Rate-Limiting Steps in Yeast Protein Translation
Open accessAbstract
Deep sequencing now provides detailed snapshots of ribosome occupancy on mRNAs. We leverage these data to parameterize a computational model of translation, keeping track of every ribosome, tRNA, and mRNA molecule in a yeast cell. We determine the parameter regimes in which fast initiation or high codon bias in a transgene increases protein yield and infer the initiation rates of endogenous Saccharomyces cerevisiae genes, which vary by several orders of magnitude and correlate with 5' mRNA folding energies. Our model recapitulates the previously reported 5'-to-3' ramp of decreasing ribosome densities, although our analysis shows that this ramp is caused by rapid initiation of short genes rather than slow codons at the start of transcripts. We conclude that protein production in healthy yeast cells is typically limited by the availability of free ribosomes, whereas protein production under periods of stress can sometimes be rescued by reducing initiation or elongation rates.
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“Some studies have shown that protein expression level drops if the 5′-end leader region has more secondary structure5,50–53.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [52]
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“Most surprising, in contrast to previous reports47–49, we found 5’ UTRs that are highly structured, such as the dengue virus (DEN2), can support efficient translation.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [49]
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- Tuller, 2010, An evolutionarily conserved mechanism for controlling the efficiency of protein translation, Cell, 141, 344, 10.1016/j.cell.2010.03.031 · DOI · Paper page
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“…translation elongation at the coding region’s 5 0 end; these investigators claimed that this earlier observed phenomenon was an artifact either of the ribosome profiling experiment (Ingolia et al., 2011) or of the data analysis, because shorter genes have higher initiation rates (Shah et al., 2013).”
BackgroundRibosome profiling: new views of translation, from single codons to genome scale
Ingolia, N. T. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3645 · Cited by 668
Metadata
- Authors
- Shah, P., Ding, Y., Niemczyk, M., Kudla, G., & Plotkin, J. B.
- Affiliations
- University of Pennsylvania (US)
- Wellcome Centre for Cell Biology (GB)
- Corresponding author
- Plotkin, Joshua B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 153
- Issue
- 7
- Pages
- 1589-1601
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3694300
- OpenAlex
- W2011503994
- Cited by
- 463
- References
- 72
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 31 · 2023: 33 · 2022: 37 · 2021: 27 · 2020: 40 · 2019: 37 · 2018: 42 · 2017: 50 · 2016: 48 · 2015: 26 · 2014: 44 · 2013: 9
- FWCI
- 18.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Burroughs Wellcome Fund
- Army Research Office (D12AP00025, W911NF-12-1-0552)
- James S. McDonnell Foundation
- David and Lucile Packard Foundation
- U.S. Department of the Interior
- Wellcome Trust (077248)
- Alfred P. Sloan Foundation (RFP-12-16)
- 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 › Genomics and Chromatin Dynamics
- Keywords
- mRNA translation, ribosome occupancy, translation initiation rate, codon usage bias, free ribosomes, protein production, Saccharomyces cerevisiae, tRNA availability, stress response
- MeSH terms
- Codon, Markov Chains, Models, Genetic, Ribosomes, RNA, Messenger, RNA, Transfer, Saccharomyces cerevisiae, Protein Biosynthesis
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