Rate-Limiting Steps in Yeast Protein Translation

Shah, Premal; Ding, Yang; Niemczyk, Malwina; Kudla, Grzegorz; Plotkin, Joshua B.

doi:10.1016/j.cell.2013.05.049

Cited by 464RNA and protein synthesis mechanismsRNA Research and SplicingGenomics and Chromatin Dynamics

Rate-Limiting Steps in Yeast Protein Translation

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Shah, Premal, Ding, Yang, Niemczyk, Malwina, Kudla, Grzegorz, Plotkin, Joshua B.·2013·Cell

DOI 10.1016/j.cell.2013.05.049PMC PMC3694300

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Abstract

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 structure.
“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]
The Results section (‘Initiation Probabilities of Endogenous Genes’; page not provided) says strong 5′ mRNA structure reduces initiation and reports an experimental link between 5′ folding and protein levels in yeast. But the paper measures folding across nucleotides −4 to +37, mostly within the coding sequence, so it does not establish the claim specifically for secondary structure in the 5′ leader region. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Highly structured 5' UTRs, such as dengue virus (DEN2), can support efficient translation, contrary to previous reports.
“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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Background
Widespread Co-translational RNA Decay Reveals Ribosome Dynamics
Pelechano, V., Wu, W., & Steinmetz, L. M. (2015) · Cell · doi:10.1016/j.cell.2015.05.008 · Cited by 325 · see citing works
“, 2014), or confounding factors, such as the rapid initiation of short genes (Shah et al., 2013).”
Background
Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor
Iwasaki, S., Floor, S. N., & Ingolia, N. T. (2016) · Nature · doi:10.1038/nature17978 · Cited by 304 · see citing works
“His-tag, MBPtag, Tobacco Etch Virus protease cleavage site, and N-terminal region of eIF4A (1-237) were cloned into pET-28a, to construct pHisMBP-eIF4A (1-237).”
Distinct stages of the translation elongation cycle revealed by sequencing ribosome-protected mRNA fragments
Lareau, L. F., Hite, D., Hogan, G. J., & Brown, P. O. (2014) · eLife · doi:10.7554/elife.01257 · Cited by 312 · see citing works
“New methods for high-throughput measurement of translation have led to renewed interest in modeling the constraints on coding sequence and the effects of codon choice on translation efficiency (Tuller et al., 2010; Plotkin and Kudla, 2011; Dana and Tuller, 2012; Charneski and Hurst, 2013; Shah et al., 2013).”
BackgroundMethod
Translation inhibitors cause abnormalities in ribosome profiling experiments
Gerashchenko, M. V., & Gladyshev, V. N. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku671 · Cited by 262 · see citing works
Altered translation of GATA1 in Diamond-Blackfan anemia
Ludwig, L. S., Gazda, H. T., Eng, J. C., Eichhorn, S. W., Thiru, P., Ghazvinian, R., George, T. I., Gotlib, J. R., Beggs, A. H., Sieff, C. A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3557 · Cited by 302 · see citing works
Cells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions
Torrent, M., Chalancon, G., de Groot, N. S., Wüster, A., & Babu, M. M. (2018) · Science Signaling · doi:10.1126/scisignal.aat6409 · Cited by 275 · see citing works
The Organizing Principles of Eukaryotic Ribosome Recruitment
Pelletier, J., & Sonenberg, N. (2019) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-013118-111042 · Cited by 261 · see citing works
“3 aa/s with a mean distance between consecutive bound ribosomes of 60 codons (221).”
Background
Ribosome profiling reveals post-transcriptional buffering of divergent gene expression in yeast
McManus, C. J., May, G. E., Spealman, P., & Shteyman, A. (2014) · Genome Research · doi:10.1101/gr.164996.113 · Cited by 219 · see citing works
“This is consistent with the common model that yeast protein synthesis is largely regulated at the translation initiation step (Lackner et al. 2007; Sonenberg and Hinnebusch 2009; Shah et al. 2013).”
Translational reprogramming in cellular stress response
Liu, B., & Qian, S. (2013) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1212 · Cited by 249 · see citing works
Codon usage of highly expressed genes affects proteome-wide translation efficiency
Frumkin, I., Lajoie, M. J., Gregg, C. J., Hornung, G., Church, G. M., & Pilpel, Y. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719375115 · Cited by 244 · see citing works
“In line with theoretical predictions (10, 27), increasing the dwell time of the ribosome during elongation reduces translation efficiency, provided the initiation rate is sufficiently high.”
BackgroundResultInfluential
Synonymous but Not Silent: The Codon Usage Code for Gene Expression and Protein Folding
Liu, Y., Yang, Q., & Zhao, F. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-071320-112701 · Cited by 242 · see citing works
“The presence of the ramp may also be due to a data analysis bias: Shorter genes have higher translation initiation rates than longer genes, and technical issues with early ribosome profiling results selected for shorter genes (60).”
Background
Quantitative profiling of initiating ribosomes in vivo
Gao, X., Wan, J., Liu, B., Ma, M., Shen, B., & Qian, S. (2014) · Nature Methods · doi:10.1038/nmeth.3208 · Cited by 238 · see citing works
Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation
Pop, C., Rouskin, S., Ingolia, N. T., Han, L., Phizicky, E. M., Weissman, J. S., & Koller, D. (2014) · Molecular Systems Biology · doi:10.15252/msb.20145524 · Cited by 238 · see citing works
“…underlying variation in elongation and translation efficiency in yeast and other organisms (Tuller et al , 2010a,b, 2011; Ingolia et al , 2011; Stadler & Fire, 2011; Qian et al , 2012; Charneski & Hurst, 2013; Shah et al , 2013; Woolstenhulme et al , 2013; Gardin et al , 2014; Lareau et al , 2014).”
Influential
Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates
Riba, A., Di Nanni, N., Mittal, N., Arhné, E., Schmidt, A., & Zavolan, M. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817299116 · Cited by 209 · see citing works
“As the high codon adaptation index exhibited by these ORFs would predict fast elongation and thereby low ribosome density (44), high ribosome density on short ORFs has also been interpreted as evidence for initiation being the main determinant of ribosome density.”
BackgroundMethodInfluential
Evaluation of 244,000 synthetic sequences reveals design principles to optimize translation in Escherichia coli
Cambray, G., Guimaraes, J. C., & Arkin, A. P. (2018) · Nature Biotechnology · doi:10.1038/nbt.4238 · Cited by 235 · see citing works
Synonymous Codons: Choose Wisely for Expression
Brule, C. E., & Grayhack, E. J. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.02.001 · Cited by 231 · see citing works
Adjacent Codons Act in Concert to Modulate Translation Efficiency in Yeast
Gamble, C. E., Brule, C. E., Dean, K., Fields, S., & Grayhack, E. J. (2016) · Cell · doi:10.1016/j.cell.2016.05.070 · Cited by 222 · see citing works
“…the 50 end of an open reading frame (ORF) can reduce translation efficiency in E. coli and S. cerevisiae (Goodman et al., 2013; Kudla et al., 2009; Shah et al., 2013; Tuller et al., 2010b), we investigated whether enrichment of each 6-mer in low-expression variants is explicable primarily by…”
Background
Understanding Biases in Ribosome Profiling Experiments Reveals Signatures of Translation Dynamics in Yeast
Hussmann, J. A., Patchett, S., Johnson, A. M., Sawyer, S. L., & Press, W. H. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005732 · Cited by 222 · see citing works
Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation
Ishimura, R., Nagy, G., Dotu, I., Chuang, J. H., & Ackerman, S. L. (2016) · eLife · doi:10.7554/elife.14295 · Cited by 221 · see citing works
“Indeed, under mild amino acid stress conditions (two–five fold decrease in tRNAs) a decrease in initiation has been predicted to also decrease protein production via yeast whole-cell modeling simulations in which ribosomes have been suggested to be rate limiting for protein production (Shah et al., 2013).”
Background
Central dogma rates and the trade-off between precision and economy in gene expression
Hausser, J., Mayo, A., Keren, L., & Alon, U. (2019) · Nature Communications · doi:10.1038/s41467-018-07391-8 · Cited by 188 · see citing works
Redefining the Translational Status of 80S Monosomes
Heyer, E. E., & Moore, M. J. (2016) · Cell · doi:10.1016/j.cell.2016.01.003 · Cited by 202 · see citing works
“Further, the average distance between elongating ribosomes in Saccharomyces cerevisiae has been estimated to be >100 nt (Arava et al., 2003; Shah et al., 2013).”
The ribosome in action: Tuning of translational efficiency and protein folding
Rodnina, M. V. (2016) · Protein Science · doi:10.1002/pro.2950 · Cited by 211 · see citing works
“A rapid turnover of ribosomes appears to be important, as protein production, for instance in yeast cells, is typically limited by the availability of free ribosomes.(55) The ribosome density on an mRNA correlates extremely well with protein abundance and provides a reliable indicator for the prediction of absolute tr…”
Background
Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation
Lapointe, C. P., Grosely, R., Johnson, A. G., Wang, J., Fernández, I. S., & Puglisi, J. D. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2017715118 · Cited by 207 · see citing works
“This lag was similar in length to the observed lifetime of the NSP1–40S subunit interaction (at least ∼250 s) and longer than the time frame of translation initiation on many mRNAs (<60 s) (61, 62), the presumptive rate-limiting phase of protein synthesis (26, 61).”
Background
Multiple roles of the coding sequence 5′ end in gene expression regulation
Tuller, T., & Zur, H. (2015) · Nucleic Acids Research · doi:10.1093/nar/gku1313 · Cited by 206 · see citing works
eIF5A facilitates translation termination globally and promotes the elongation of many non polyproline-specific tripeptide sequences
Pelechano, V., & Alepuz, P. M. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx479 · Cited by 191 · see citing works
Disome and Trisome Profiling Reveal Genome-wide Targets of Ribosome Quality Control
Meydan, S., & Guydosh, N. R. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.06.010 · Cited by 187 · see citing works
“, 2018) and in yeast (Shah et al., 2013), a slowdown > 5-fold by the leading ribosome was predicted to cause formation of disomes (Juszkiewicz et al.”
Background
Quantitative nature of overexpression experiments
Moriya, H. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-07-0512 · Cited by 172 · see citing works
“The effect becomes apparent when the cellular resources for protein turnover, especially the ribosomes producing other proteins, are overstretched, monopolized by a strong expression of unnecessary proteins (Stoebel et al., 2008; Shachrai et al., 2010; Shah et al., 2013).”
Background
RNA G-quadruplexes at upstream open reading frames cause DHX36- and DHX9-dependent translation of human mRNAs
Murat, P., Marsico, G., Herdy, B., Ghanbarian, A. T., Portella, G., & Balasubramanian, S. (2018) · Genome biology · doi:10.1186/s13059-018-1602-2 · Cited by 166 · see citing works
Evolution at two levels of gene expression in yeast
Artieri, C. G., & Fraser, H. B. (2014) · Genome Research · doi:10.1101/gr.165522.113 · Cited by 138 · see citing works
“The presence of mRNA secondary structure in the vicinity of the start codon has also been implicated in reducing translational efficiency (Kudla et al. 2009; Robbins-Pianka et al. 2010; Bentele et al. 2013; Dvir et al. 2013; Goodman et al. 2013; Shah et al. 2013).”
Background
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 163 · see citing works
“, 1996), overexpressed transgenes are likely to perturb the balance between codon usage and tRNA abundance, creating a global translation defect (Shah et al., 2013).”
Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae
Dever, T. E., Kinzy, T. G., & Pavitt, G. D. (2016) · Genetics · doi:10.1534/genetics.115.186221 · Cited by 143 · see citing works
“A rapidly dividing yeast cell growing on rich medium is estimated to synthesize nearly 13,000 proteins per second (von der Haar 2008), limited by the availability of ribosomes (Shah et al. 2013).”
Background
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 145 · see citing works
“While the advantage for codon bias is not obvious, it has been suggested, for example, that codon usage optimizes global, rather than local translation (124).”
An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repressionPreprint
Ogami, K., Richard, P., Chen, Y., Hoque, M., Li, W., Moresco, J. J., Yates, J. R., Tian, B., & Manley, J. L. (2017) · Genes & Development · doi:10.1101/gad.302604.117 · Cited by 143 · see citing works
“Indeed, studies in yeast have suggested that ribosomes in fact are limiting for translation (Chu and von der Haar 2012; Shah et al. 2013).”
Background
Exploring the potential of Saccharomyces cerevisiae for biopharmaceutical protein production
Wang, G., Huang, M., & Nielsen, J. (2017) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2017.03.017 · Cited by 142 · see citing works
“In addition, protein production in yeast cells might be typically limited by the availability of free ribosomes under specific conditions [31,32].”
An Integrated Approach Reveals Regulatory Controls on Bacterial Translation Elongation
Subramaniam, A. R., Zid, B. M., & O’Shea, E. K. (2014) · Cell · doi:10.1016/j.cell.2014.10.043 · Cited by 141 · see citing works
“We observed a similar effect of intraribosomal events when we simulated a model for yeast translation (Shah et al., 2013) (Figure S2A).”
Influential
Accounting for biases in riboprofiling data indicates a major role for proline in stalling translationPreprint
Artieri, C. G., & Fraser, H. B. (2014) · Genome Research · doi:10.1101/gr.175893.114 · Cited by 133 · see citing works
“2009; Goodman et al. 2013; Shah et al. 2013).”
Background
Imaging mRNA In Vivo, from Birth to Death
Tutucci, E., Livingston, N. M., Singer, R. H., & Wu, B. (2018) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-070317-033037 · Cited by 133 · see citing works
Role of mRNA structure in the control of protein folding
Faure, G., Ogurtsov, A. Y., Shabalina, S. A., & Koonin, E. V. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw671 · Cited by 134 · see citing works
Does functional specialization of ribosomes really exist?
Ferretti, M., & Karbstein, K. (2019) · RNA · doi:10.1261/rna.069823.118 · Cited by 130 · see citing works
“Because initiation is the limiting step in translation (Lackner et al. 2007; Shah et al. 2013), and involves association of ribosomal subunits with themRNA, first principle considerations suggest that initiation rates (for all mRNAs) should be proportional to ribosome concentrations.”
Background
Cotranscriptional events in eukaryotic ribosome synthesis
Turowski, T. W., & Tollervey, D. W. (2014) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1263 · Cited by 130 · see citing works
“Despite substantial progress in understanding the cotranscriptional events in ribosome synthesis, many outstanding questions remain: (1) How do the SSU and/or LSU processome complexes communicate with Pol I? (2) What intermediates during ribosome synthesis are subject to surveillance? (3) How is the timing of pre-40S…”
Background
The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs
Thompson, M. K., Rojas-Durán, M. F., Gangaramani, P., & Gilbert, W. V. (2016) · eLife · doi:10.7554/elife.11154 · Cited by 120 · see citing works
“Among the tested attributes, ORF length was notably well-correlated with DTE in asc1M1X (r=0.27, p=10–84, Table 1) and ORFs 500 nts were the most strongly affected (Figure 3A).”
BackgroundInfluential
The ribosome, (slow) beating heart of cancer (stem) cell
Bastide, A., & David, A. (2018) · Oncogenesis · doi:10.1038/s41389-018-0044-8 · Cited by 119 · see citing works
The Growing Toolbox for Protein Synthesis Studies
Iwasaki, S., & Ingolia, N. T. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.05.004 · Cited by 113 · see citing works
Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation
Wang, J., Shin, B., Alvarado, C., Kim, J.-R., Bohlen, J., Dever, T. E., & Puglisi, J. D. (2022) · Cell · doi:10.1016/j.cell.2022.10.005 · Cited by 116 · see citing works
Dissimilation of synonymous codon usage bias in virus–host coevolution due to translational selection
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 115 · see citing works
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. R. (2020) · Cell Systems · doi:10.1016/j.cels.2020.03.001 · Cited by 106 · see citing works
“In bacteria and yeast, strong mRNA folding near the start codon prevents ribosome binding and reduces translation efficiency, resulting in selection against strongly folded 50 mRNA regions (Kudla et al., 2009; Shah et al., 2013).”
BackgroundResultSelf-citation
Comparative survey of the relative impact of mRNA features on local ribosome profiling read density
O’Connor, P. B. F., Andreev, D. E., & Baranov, P. V. (2016) · Nature Communications · doi:10.1038/ncomms12915 · Cited by 108 · see citing works
Gene Architectures that Minimize Cost of Gene Expression
Frumkin, I., Schirman, D., Rotman, A., Li, F., Zahavi, L., Mordret, E., Asraf, O., Wu, S., Levy, S. F., & Pilpel, Y. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.11.007 · Cited by 103 · see citing works
“Recent works showed that 50 mRNA secondary structure governs expression level of transcripts in bacteria (Goodman et al., 2013; Kudla et al., 2009; Shah et al., 2013).”
The impact of ribosomal interference, codon usage, and exit tunnel interactions on translation elongation rate variation
Duc, K. D., & Song, Y. S. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007166 · Cited by 100 · see citing works
Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity
Teng, T., Mercer, C. A., Hexley, P., Thomas, G., & Fumagalli, S. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01174-13 · Cited by 98 · see citing works
“Recent studies have argued that the rate-limiting component ねぬは in protein synthesis is ribosome availability and transcripts possessing a short 5’UTR ねぬば essentially out compete longer transcripts with highly structured 5’ UTRs (60).”
BackgroundInfluential
Accurate design of translational output by a neural network model of ribosome distribution
Tunney, R. J., McGlincy, N. J., Graham, M. E., Naddaf, N., Pachter, L. S., & Lareau, L. F. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0080-2 · Cited by 96 · see citing works
tRNA Metabolism and Neurodevelopmental Disorders
Schaffer, A. E., Pinkard, O. W., & Coller, J. M. (2019) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083118-015334 · Cited by 92 · see citing works
Transcript level and sequence determinants of protein abundance and noise in Escherichia coli
Guimaraes, J. C., Rocha, M., & Arkin, A. P. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku126 · Cited by 94 · see citing works
Fine-Tuning of Hydrophobicity in Amphiphilic Polyaspartamide Derivatives for Rapid and Transient Expression of Messenger RNA Directed Toward Genome Engineering in Brain
Kim, H. J., Ogura, S., Otabe, T., Kamegawa, R., Sato, M., Kataoka, K., & Miyata, K. (2019) · ACS Central Science · doi:10.1021/acscentsci.9b00843 · Cited by 91 · see citing works
Entrainment to Periodic Initiation and Transition Rates in a Computational Model for Gene Translation
Michael Margaliot, A., Sontag, E. D., & Tuller, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096039 · Cited by 90 · see citing works
Deciphering the rules by which dynamics of mRNA secondary structure affect translation efficiency in Saccharomyces cerevisiae
Mao, Y., Liu, H., Liu, Y., & Tao, S. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku159 · Cited by 90 · see citing works
METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation
Xue, M., Dong, L., Zhang, H., Li, Y., Qiu, K., Zhao, Z., Gao, M., Han, L., Chan, A., Li, W., et al. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01526-9 · Cited by 89 · see citing works
“Of the four different steps, translation initiation is generally the rate-limiting event [13].”
Background
Yeast eIF4A enhances recruitment of mRNAs regardless of their structural complexity
Yourik, P., Aitken, C. E., Zhou, F., Gupta, N., Hinnebusch, A. G., & Lorsch, J. R. (2017) · eLife · doi:10.7554/elife.31476 · Cited by 85 · see citing works
“…et al., 2015; Lorsch and Herschlag, 1998b; Rajagopal et al., 2012; Rogers et al., 1999) and it is unclear whether it could support in vivo rates of translation initiation in the range of 10 min 1 (Palmiter, 1975; Shah et al., 2013; Siwiak and Zielenkiewicz, 2010) if this is its function.”
Exaptive Evolution of Target of Rapamycin Signaling in Multicellular Eukaryotes
Brunkard, J. O. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.022 · Cited by 84 · see citing works
“These considerable resources are devoted to ribosomes because ribosome abundance is, except under extreme nutrient deprivation, rate limiting for protein synthesis and organismal growth (Shah et al., 2013).”
Background
Transcriptional response of Prochlorococcus to co-culture with a marine Alteromonas: differences between strains and the involvement of putative infochemicals
Aharonovich, D., & Sher, D. (2016) · The ISME Journal · doi:10.1038/ismej.2016.70 · Cited by 86 · see citing works
“Recent studies in eukaryotes have shown that short genes are transcribed and translated rapidly compared with longer genes, perhaps providing a mechanism for fast response to changes in conditions or during development (Shah et al., 2013; Heyn et al., 2014).”
Background
Impacts of uORF codon identity and position on translation regulation
Lin, Y., May, G. E., Kready, H., Nazzaro, L., Mao, M., Spealman, P., Creeger, Y., & McManus, C. J. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz681 · Cited by 85 · see citing works
“Previous studies indicated that codon effects on expression from main ORFs are correlated with the abundance of complementary tRNA (32,33), and that the effects of repressive dicodon pairs could be alleviated by overexpressing tRNA complementary to the corresponding codons (16).”
Background
The molecular basis of mTORC1-regulated translation
Thoreen, C. C. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160072 · Cited by 79 · see citing works
eIF5B gates the transition from translation initiation to elongation
Wang, J., Johnson, A. G., Lapointe, C. P., Choi, J., Prabhakar, A., Chen, D.-H., Petrov, A. N., & Puglisi, J. D. (2019) · Nature · doi:10.1038/s41586-019-1561-0 · Cited by 83 · see citing works
Estimating the protein burden limit of yeast cells by measuring the expression limits of glycolytic proteins
Eguchi, Y., Makanae, K., Hasunuma, T., Ishibashi, Y., Kito, K., & Moriya, H. (2018) · eLife · doi:10.7554/elife.34595 · Cited by 81 · see citing works
“According to the protein-burden concept (Dong et al., 1995; Kafri et al., 2016; Shah et al., 2013; Snoep et al., 1995; Stoebel et al., 2008), the ultimate overexpression of any protein could cause growth defects by overloading basic protein production resources.”
Background
Single Molecule Fluorescence Approaches Shed Light on Intracellular RNAs
Pitchiaya, S., Heinicke, L. A., Custer, T. C., & Walter, N. G. (2014) · Chemical Reviews · doi:10.1021/cr400496q · Cited by 80 · see citing works
RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3
Bastide, A., Peretti, D., Knight, J. R. P., Grosso, S., Spriggs, R. V., Pichon, X., Sbarrato, T., Roobol, A., Roobol, J., Vito, D., et al. (2017) · Current Biology · doi:10.1016/j.cub.2017.01.047 · Cited by 76 · see citing works
A rare codon-based translational program of cell proliferation
Guimaraes, J. C., Mittal, N., Gnann, A., Jedlinski, D., Riba, A., Buczak, K., Schmidt, A., & Zavolan, M. (2020) · Genome biology · doi:10.1186/s13059-020-1943-5 · Cited by 72 · see citing works
“This would be a reflection of translation elongation being most limited for rare codon-enriched transcripts in cells when the overall elongation machinery is reduced, such as cells growing at low proliferation rates [33, 34, 39, 50, 51].”
Background
Predictive biophysical modeling and understanding of the dynamics of mRNA translation and its evolution
Zur, H., & Tuller, T. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw764 · Cited by 73 · see citing works
“Various studies assumed and suggested that this issue is a major determinant shaping coding regions and organismal evolution (19,46,51,54,62,66,68–69, Additional facets explored included understanding the translation regimes in various genes, and the explanations to observed variables such as…”
BackgroundInfluential
Specialized ribosomes and the control of translation
Guo, H. (2018) · Biochemical Society Transactions · doi:10.1042/bst20160426 · Cited by 72 · see citing works
A chemical kinetic basis for measuring translation initiation and elongation rates from ribosome profiling data
Sharma, A. K., Sormanni, P., Ahmed, N., Ciryam, P., Friedrich, U. A., Kramer, G., & O’Brien, E. P. (2019) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1007070 · Cited by 68 · see citing works
“the rate limiting step in translation [21].”
BackgroundMethodResultInfluential
Bacteria differently regulate mRNA abundance to specifically respond to various stresses
Bartholomäus, A., Fedyunin, I., Feist, P., Sin, C., Zhang, G., Valleriani, A., & Ignatova, Z. (2016) · Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences · doi:10.1098/rsta.2015.0069 · Cited by 81 · see citing works
“Under normal conditions more than 90% of the ribosomes are involved in translation [52,53] thus leaving little capacity to reallocate ribosomes to new mRNAs [54].”
Background
Genetic Influences on Translation in Yeast
Albert, F. W., Muzzey, D., Weissman, J. S., & Kruglyak, L. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004692 · Cited by 72 · see citing works
“[47]) will be needed to further address this question.”
Background
Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F
Chu, J., Zhang, W., Cencic, R., O’Connor, P. B. F., Robert, F., Devine, W. G., Selznick, A., Henkel, T. O., Merrick, W. C., Brown, L. E., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.002 · Cited by 74 · see citing works
“The increased eIF4F residence time on the polypurine RNA in the presence of rocaglate is longer than the rates of translation initiation (median < 1 min) (Shah et al., 2013; Yan et al., 2016).”
Background
Reaching the limit
Bolognesi, B., & Lehner, B. (2018) · eLife · doi:10.7554/elife.39804 · Cited by 73 · see citing works
Secondary structures in RNA synthesis, splicing and translation
Georgakopoulos‐Soares, I., Parada, G. E., & Hemberg, M. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.05.041 · Cited by 74 · see citing works
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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.
ORCID: Shah, Premal
Ding, Yang
Kudla, Grzegorz
Plotkin, Joshua B.
Venue: Cell
Publisher: Elsevier BV
Published: 2013-06
Volume: 153
Issue: 7
Pages: 1589-1601
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2013.05.049
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/3.0/ (vor, 45 d)
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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