An Evolutionarily Conserved Mechanism for Controlling the Efficiency of Protein Translation

Tuller, Tamir; Carmi, Asaf; Vestsigian, Kalin; Navon, Sivan; Dorfan, Yuval; Zaborske, John M.; Pan, Tao; Dahan, Orna; Furman, Itay; Pilpel, Yitzhak

doi:10.1016/j.cell.2010.03.031

Cited by 803 publications

(1,176 citation statements)

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“…Tuller et al predicted that the speed of translation is slower during the first 30-50 codons, named the 'ramp', and then increases to a steady speed for the rest of the mRNA (Figure 1) (Tuller et al 2010). The ramp has been hypothesized to slow translation elongation immediately after initiation, to facilitate uniform spacing between ribosomes and prevent congestion along the mRNA.…”

Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

“…This is suggested to allow rapid release and recycling of the initiator tRNA, which is required as initiation is the rate-limiting step of translation (Tuller et al 2010). …”

Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

“…This may lead to ribosome congestion on the mRNA and premature termination (Fredrick & Ibba 2010;Tuller et al 2010). …”

Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

See 2 more Smart Citations

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Webster

Teh

K.‐C.

2016

Biotech & Bioengineering

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Degeneracy in the genetic code allows multiple codon sequences to encode the same protein. Codon usage bias in genes is the term given to the preferred use of particular synonymous codons. Synonymous codon substitutions had been regarded as "silent" as the primary structure of the protein was not affected; however, it is now accepted that synonymous substitutions can have a significant effect on heterologous protein expression. Codon optimization, the process of altering codons within the gene sequence to improve recombinant protein expression, has become widely practised.Multiple inter-linked factors affecting protein expression need to be taken into consideration when optimizing a gene sequence. Over the years, various computer programmes have been developed to aid in the gene sequence optimization process. However, as the rulebook for altering codon usage to affect protein expression is still not completely understood, it is difficult to predict which strategy, if any, will design the 'optimal' gene sequence.In this review, codon usage bias and factors affecting codon selection will be discussed and the evidence for codon optimization impact will be reviewed for recombinant protein expression using plants as a case study. These developments will be relevant to all recombinant expression systems, however, molecular pharming in plants is an area which has consistently encountered difficulties with low levels of recombinant protein expression, and should benefit from an evidence based rational approach to synthetic gene design. This article is protected by copyright. All rights reserved

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Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

“…This is suggested to allow rapid release and recycling of the initiator tRNA, which is required as initiation is the rate-limiting step of translation (Tuller et al 2010). …”

Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

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Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Webster

Teh

K.‐C.

2016

Biotech & Bioengineering

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“…At the level of a single microbial genome, the effect of CU bias is routinely used to predict for functionally relevant and highly expressed genes (26)(27)(28). The choice of preferred codons in a single genome is most closely correlated with abundance of the cognate tRNA molecules (29)(30)(31) and further influenced by the genome's GC content (32,33).…”

Section: Introductionmentioning

confidence: 99%

Environmental Shaping of Codon Usage and Functional Adaptation Across Microbial Communities

Lucić¹,

Roller²,

Nágy³

et al. 2015

Encyclopedia of Metagenomics

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Microbial communities represent the largest portion of the Earth's biomass. Metagenomics projects use high-throughput sequencing to survey these communities and shed light on genetic capabilities that enable microbes to inhabit every corner of the biosphere. Metagenome studies are generally based on (i) classifying and ranking functions of identified genes; and (ii) estimating the phyletic distribution of constituent microbial species. To understand microbial communities at the systems level, it is necessary to extend these studies beyond the species' boundaries and capture higher levels of metabolic complexity. We evaluated 11 metagenome samples and demonstrated that microbes inhabiting the same ecological niche share common preferences for synonymous codons, regardless of their phylogeny. By exploring concepts of translational optimization through codon usage adaptation, we demonstrated that community-wide bias in codon usage can be used as a prediction tool for lifestyle-specific genes across the entire microbial community, effectively considering microbial communities as meta-genomes. These findings set up a 'functional metagenomics' platform for the identification of genes relevant for adaptations of entire microbial communities to environments. Our results provide valuable arguments in defining the concept of microbial species through the context of their interactions within the community.

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“…These observations suggest that codon use plays a poorly understood role in regulating protein expression. Several hypotheses attempt to explain how codon use mediates this effect, including but not limited to facilitating ribosomal pausing early in translation to optimize protein folding (13); adjusting mRNA secondary structure to optimize translation initiation or to modulate mRNA degradation; preventing ribosome stalling by coevolving with tRNA levels (6); providing a "translational ramp" for proper ribosome spacing and effective translation (14); and providing a layer of translational regulation for independent control of each gene in an operon (15). Additionally, codon use may impact translational fidelity (16), and the proteome may be tuned by fine control of the decoding tRNA pools (17).…”

mentioning

confidence: 99%

Emergent rules for codon choice elucidated by editing rare arginine codons in Escherichia coli

Napolitano

Landon

Gregg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The degeneracy of the genetic code allows nucleic acids to encode amino acid identity as well as noncoding information for gene regulation and genome maintenance. The rare arginine codons AGA and AGG (AGR) present a case study in codon choice, with AGRs encoding important transcriptional and translational properties distinct from the other synonymous alternatives (CGN). We created a strain of Escherichia coli with all 123 instances of AGR codons removed from all essential genes. We readily replaced 110 AGR codons with the synonymous CGU codons, but the remaining 13 "recalcitrant" AGRs required diversification to identify viable alternatives. Successful replacement codons tended to conserve local ribosomal binding site-like motifs and local mRNA secondary structure, sometimes at the expense of amino acid identity. Based on these observations, we empirically defined metrics for a multidimensional "safe replacement zone" (SRZ) within which alternative codons are more likely to be viable. To evaluate synonymous and nonsynonymous alternatives to essential AGRs further, we implemented a CRISPR/Cas9-based method to deplete a diversified population of a wild-type allele, allowing us to evaluate exhaustively the fitness impact of all 64 codon alternatives. Using this method, we confirmed the relevance of the SRZ by tracking codon fitness over time in 14 different genes, finding that codons that fall outside the SRZ are rapidly depleted from a growing population. Our unbiased and systematic strategy for identifying unpredicted design flaws in synthetic genomes and for elucidating rules governing codon choice will be crucial for designing genomes exhibiting radically altered genetic codes.codon choice | genome editing | recoded genomes

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An Evolutionarily Conserved Mechanism for Controlling the Efficiency of Protein Translation

Cited by 803 publications

References 50 publications

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Environmental Shaping of Codon Usage and Functional Adaptation Across Microbial Communities

Emergent rules for codon choice elucidated by editing rare arginine codons in Escherichia coli

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