Genes adopt non‐optimal codon usage to generate cell cycle‐dependent oscillations in protein levels

Frenkel‐Morgenstern, Milana; Danon, Tamar; Christian, Tom; Igarashi, Tadashi; Cohen, Lydia; Hou, Ya‐Ming; Jensen, Lars Juhl

doi:10.1038/msb.2012.3

Cited by 125 publications

(145 citation statements)

References 65 publications

(104 reference statements)

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“…HAV codon usage constitutes an additional example of what seems to be a broader phenomenon, as revealed by the role of nonoptimal codons in the control of the circadian cycle of both prokaryotes (71) and eukaryotes (72) or even the cell cycle in eukaryotes (73).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis A Virus Adaptation to Cellular Shutoff Is Driven by Dynamic Adjustments of Codon Usage and Results in the Selection of Populations with Altered Capsids

Costafreda

Pérez-Rodríguez

D’Andrea

et al. 2014

J Virol

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Hepatitis A virus (HAV) has a highly biased and deoptimized codon usage compared to the host cell and fails to inhibit host protein synthesis. It has been proposed that an optimal combination of abundant and rare codons controls the translation speed required for the correct capsid folding. The artificial shutoff host protein synthesis results in the selection of variants containing mutations in the HAV capsid coding region critical for folding, stability, and function. Here, we show that these capsid mutations resulted in changes in their antigenicity; in a reduced stability to high temperature, low pH, and biliary salts; and in an increased efficacy of cell entry. In conclusion, the adaptation to cellular shutoff resulted in the selection of large-plaque-producing virus populations. IMPORTANCEHAV has a naturally deoptimized codon usage with respect to that of its cell host and is unable to shut down the cellular translation. This fact contributes to the low replication rate of the virus, in addition to other factors such as the highly inefficient internal ribosome entry site (IRES), and explains the outstanding physical stability of this pathogen in the environment mediated by a folding-dependent highly cohesive capsid. Adaptation to artificially induced cellular transcription shutoff resulted in a redeoptimization of its capsid codon usage, instead of an optimization. These genomic changes are related to an overall change of capsid folding, which in turn induces changes in the cell entry process. Remarkably, the adaptation to cellular shutoff allowed the virus to significantly increase its RNA uncoating efficiency, resulting in the selection of large-plaque-producing populations. However, these populations produced much-debilitated virions.

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Section: Discussionmentioning

confidence: 99%

Hepatitis A Virus Adaptation to Cellular Shutoff Is Driven by Dynamic Adjustments of Codon Usage and Results in the Selection of Populations with Altered Capsids

Costafreda

Pérez-Rodríguez

D’Andrea

et al. 2014

J Virol

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“…For example, concentrations of tRNAs and aminoacyl-tRNA synthetases have been demonstrated to oscillate during the human cell cycle (Frenkel-Morgenstern et al, 2012). As a consequence, gene sets that are expressed at different phases of the cell cycle have different codon usage (Frenkel-Morgenstern et al, 2012). This provides a codon bias strategy that supports cell-cycle regulation.…”

Section: Intergenic Codon Bias and Differential Expressionmentioning

confidence: 99%

Codon Bias as a Means to Fine-Tune Gene Expression

et al. 2015

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The redundancy of the genetic code implies that most amino acids are encoded by multiple synonymous codons. In all domains of life, a biased frequency of synonymous codons is observed at the genome level, in functionally related genes (e.g., in operons), and within single genes. Other codon bias variants include biased codon pairs and codon co-occurrence. Although translation initiation is the key step in protein synthesis, it is generally accepted that codon bias contributes to translation efficiency by tuning the elongation rate of the process. Moreover, codon bias plays an important role in controlling a multitude of cellular processes, ranging from differential protein production to protein folding. Here we review currently known types of codon bias and how they may influence translation. We discuss how understanding the principles of codon bias and translation can contribute to improved protein production and developments in synthetic biology.

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“…First, there is evidence that in some cases the rates λ, λ i are time-varying and that they change in a periodic fashion [64]. It may be interesting to analyze the behavior of the RFM or HRFM in this case.…”

Section: Discussionmentioning

confidence: 99%

“…In practice, it is not clear yet how many genes are translated in the elongation limited regime and how many in the initiation limiting regime. However, we believe that both regimes occur in nature depending on the organism and, more importantly, on various biological conditions (see, for example, [10], [39], [40], [41]). …”

Section: Discussionmentioning

confidence: 99%

“…the relative concentration of tRNA molecules and elongation factors, the number of available ribosomes and the number of mRNA molecules) may vary significantly among different tissues, conditions, and organisms [10], [39], [40], [41]. Thus, it is possible that each of the apparently contradicting theories is indeed dominant in a specific regime.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

On the Steady-State Distribution in the Homogeneous Ribosome Flow Model

Margaliot

Tuller

2012

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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We consider the steady-state distribution of the HRFM. We provide formulas that relate the different parameters of the model in steadystate. We prove the following properties: 1) the ribosomal density profile is monotonically decreasing along the coding sequence; 2) the ribosomal density at each codon monotonically increases with the initiation rate; and 3) for a constant initiation rate, the translation rate monotonically decreases with the length of the coding sequence. In addition, we analyze the translation rate of the HRFM at the limit of very high and very low initiation rate, and provide explicit formulas for the translation rate in these two cases. We discuss the relationship between these theoretical results and biological findings on the translation process.

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Genes adopt non‐optimal codon usage to generate cell cycle‐dependent oscillations in protein levels

Abstract: Most cell cycle-regulated genes adopt non-optimal codon usage, namely, their translation involves wobbly matching codons. Here, the authors show that tRNA expression is cyclic and that codon usage, therefore, can give rise to cell-cycle regulation of proteins.

Cited by 125 publications

References 65 publications

Hepatitis A Virus Adaptation to Cellular Shutoff Is Driven by Dynamic Adjustments of Codon Usage and Results in the Selection of Populations with Altered Capsids

Hepatitis A Virus Adaptation to Cellular Shutoff Is Driven by Dynamic Adjustments of Codon Usage and Results in the Selection of Populations with Altered Capsids

Codon Bias as a Means to Fine-Tune Gene Expression

On the Steady-State Distribution in the Homogeneous Ribosome Flow Model

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