scholarly journals Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Zhipeng Zhou ◽  
Yunkun Dang ◽  
Mian Zhou ◽  
Haiyan Yuan ◽  
Yi Liu
Keyword(s):  
Protein Expression ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Transcription Termination ◽  
Model Organism ◽  
Open Reading Frames ◽  
Strong Negative Correlation ◽  
Rare Codons ◽  
Cleavage And Polyadenylation ◽  
Mouse Cells

Codon usage biases are found in all genomes and influence protein expression levels. The codon usage effect on protein expression was thought to be mainly due to its impact on translation. Here, we show that transcription termination is an important driving force for codon usage bias in eukaryotes. Using Neurospora crassa as a model organism, we demonstrated that introduction of rare codons results in premature transcription termination (PTT) within open reading frames and abolishment of full-length mRNA. PTT is a wide-spread phenomenon in Neurospora, and there is a strong negative correlation between codon usage bias and PTT events. Rare codons lead to the formation of putative poly(A) signals and PTT. A similar role for codon usage bias was also observed in mouse cells. Together, these results suggest that codon usage biases co-evolve with the transcription termination machinery to suppress premature termination of transcription and thus allow for optimal gene expression.

scholarly journals Overcoming codon-usage bias in heterologous protein expression in Streptococcus gordonii

Microbiology ◽  
2009 ◽  
Vol 155 (11) ◽  
pp. 3581-3588 ◽  
Author(s):  
Song F. Lee ◽  
Yi-Jing Li ◽  
Scott A. Halperin
Keyword(s):  
Protein Expression ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Heterologous Protein ◽  
Trna Gene ◽  
Heterologous Protein Expression ◽  
Streptococcus Gordonii ◽  
Heterologous Proteins ◽  
Single Chain ◽  
Rare Codons

One of the limitations facing the development of Streptococcus gordonii into a successful vaccine vector is the inability of this bacterium to express high levels of heterologous proteins. In the present study, we have identified 12 codons deemed as rare codons in S. gordonii and seven other streptococcal species. tRNA genes encoding 10 of the 12 rare codons were cloned into a plasmid. The plasmid was transformed into strains of S. gordonii expressing the fusion protein SpaP/S1, the anti-complement receptor 1 (CR1) single-chain variable fragment (scFv) antibody, or the Toxoplasma gondii cyclophilin C18 protein. These three heterologous proteins contained high percentages of amino acids encoded by rare codons. The results showed that the production of SpaP/S1, anti-CR1 scFv and C18 increased by 2.7-, 120- and 10-fold, respectively, over the control strains. In contrast, the production of the streptococcal SpaP protein without the pertussis toxin S1 fragment was not affected by tRNA gene supplementation, indicating that the increased production of SpaP/S1 protein was due to the ability to overcome the limitation caused by rare codons required for the S1 fragment. The increase in anti-CR1 scFv production was also observed in Streptococcus mutans following tRNA gene supplementation. Collectively, the findings in the present study demonstrate for the first time, to the best of our knowledge, that codon-usage bias exists in Streptococcus spp. and the limitation of heterologous protein expression caused by codon-usage bias can be overcome by tRNA supplementation.

scholarly journals Distinct responses to rare codons in select Drosophila tissues

2022 ◽  
Author(s):  
Scott R. Allen ◽  
Rebeccah K Stewart ◽  
Michael Rogers ◽  
Ivan Jimenez Ruiz ◽  
Erez Cohen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Critical Role ◽  
Specific Protein ◽  
Human Testis ◽  
Rare Codon ◽  
Tissue Specific ◽  
Rare Codons ◽  
Drosophila Testis

Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index, to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in restricting protein expression of an evolutionarily young gene, RpL10Aa, to the Drosophila testis. Rare codon-mediated restriction of this testis-specific protein is critical for female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.

scholarly journals A New Look at Codon Usage and Protein Expression

10.29007/d4tz ◽  
2019 ◽  
Author(s):  
Gabriel Wright ◽  
Anabel Rodriguez ◽  
Patricia Clark ◽  
Scott Emrich
Keyword(s):  
Protein Expression ◽  
Codon Usage ◽  
Empirical Data ◽  
Codon Usage Bias ◽  
Elongation Rate ◽  
Translation Rate ◽  
Translation Elongation ◽  
Promising Alternative ◽  
Highly Expressed Genes ◽  
Adaptation Index

%MinMax, a model of intra-gene translational elongation rate, relies on codon usage frequencies. Historically, %MinMax has used tables that measure codon usage bias for all genes in an organism, such as those found at HIVE-CUT. In this paper, we provide evidence that codon usage bias based on all genes is insufficient to accurately measure absolute translation rate. We show that alternative ”High-φ” codon usage tables, generated by another model (ROC-SEMPPR), are a promising alternative. By creating a hybrid model, future codon usage analyses and their applications (e.g., codon harmonization) are likely to more accurately measure the ”tempo” of translation elongation. We also suggest a High- φ alternative to the Codon Adaptation Index (CAI), a classic metric of codon usage bias based on highly expressed genes. Significantly, our new alternative is equally well correlated with empirical data as traditional CAI without using experimentally determined expression counts as input.

scholarly journals Comprehensive Analysis and Comparison on the Codon Usage Pattern of Whole Mycobacterium tuberculosis Coding Genome from Different Area

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Li Gun ◽  
Ren Yumiao ◽  
Pan Haixian ◽  
Zhang Liang
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Gc Content ◽  
Codon Usage Pattern ◽  
Usage Pattern ◽  
Strong Negative Correlation ◽  
Synonymous Codons ◽  
The Relationship ◽  
Adaptation Index

Phenomenon of unequal use of synonymous codons in Mycobacterium tuberculosis is common. Codon usage bias not only plays an important regulatory role at the level of gene expression, but also helps in improving the accuracy and efficiency of translation. Meanwhile, codon usage pattern of Mycobacterium tuberculosis genome is important for interpreting evolutionary characteristics in species. In order to investigate the codon usage pattern of the Mycobacterium tuberculosis genome, 12 Mycobacterium tuberculosis genomes from different area are downloaded from the GeneBank. The correlations between G3, GC12, whole GC content, codon adaptation index, codon bias index, and so on of Mycobacterium tuberculosis genomes are calculated. The ENC-plot, relationship between A3/(A3+T3) and G3/(G3+C3), GC12 versus GC3 plot, and the RSCU of overall/separated genomes all show that the codon usage bias exists in all 12 Mycobacterium tuberculosis genomes. Lastly, relationship between CBI and the equalization of ENC shows a strong negative correlation between them. The relationship between protein length and GC content (GC3 and GC12) shows that more obvious differences in the GC content may be in shorter protein. These results show that codon usage bias existing in the Mycobacterium tuberculosis genomes could be used for further study on their evolutionary phenomenon.

scholarly journals Codon usage regulates human KRAS expression at both transcriptional and translational levels

2018 ◽  
Vol 293 (46) ◽  
pp. 17929-17940 ◽  
Author(s):  
Jingjing Fu ◽  
Yunkun Dang ◽  
Christopher Counter ◽  
Yi Liu
Keyword(s):  
Protein Folding ◽  
Protein Expression ◽  
Codon Usage ◽  
Cell Lines ◽  
Cancer Biology ◽  
Wide Spectrum ◽  
Mrna Translation ◽  
Translation Efficiency ◽  
Rare Codons ◽  
High Amino Acid

KRAS and HRAS are highly homologous oncogenic Ras GTPase family members that are mutated in a wide spectrum of human cancers. Despite having high amino acid identity, KRAS and HRAS have very different codon usage biases: the HRAS gene contains many common codons, and KRAS is enriched for rare codons. Rare codons in KRAS suppress its protein expression, which has been shown to affect both normal and cancer biology in mammals. Here, using HRAS or KRAS expression in different human cell lines and in vitro transcription and translation assays, we show that KRAS rare codons inhibit both translation efficiency and transcription and that the contribution of these two processes varies among different cell lines. We observed that codon usage regulates mRNA translation efficiency such that WT KRAS mRNA is poorly translated. On the other hand, common codons increased transcriptional rates by promoting activating histone modifications and recruitment of transcriptional coactivators. Finally, we found that codon usage also influences KRAS protein conformation, likely because of its effect on co-translational protein folding. Together, our results reveal that codon usage has multidimensional effects on protein expression, ranging from effects on transcription to protein folding in human cells.

scholarly journals eRF1 mediates codon usage effects on mRNA translation efficiency through premature termination at rare codons

2019 ◽  
Vol 47 (17) ◽  
pp. 9243-9258 ◽  
Author(s):  
Qian Yang ◽  
Chien-Hung Yu ◽  
Fangzhou Zhao ◽  
Yunkun Dang ◽  
Cheng Wu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Codon Usage ◽  
Premature Termination ◽  
Translation Termination ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Translation Efficiency ◽  
Expression Levels ◽  
Rare Codons ◽  
Drosophila Cells

Abstract Codon usage bias is a universal feature of eukaryotic and prokaryotic genomes and plays an important role in regulating gene expression levels. A major role of codon usage is thought to regulate protein expression levels by affecting mRNA translation efficiency, but the underlying mechanism is unclear. By analyzing ribosome profiling results, here we showed that codon usage regulates translation elongation rate and that rare codons are decoded more slowly than common codons in all codon families in Neurospora. Rare codons resulted in ribosome stalling in manners both dependent and independent of protein sequence context and caused premature translation termination. This mechanism was shown to be conserved in Drosophila cells. In both Neurospora and Drosophila cells, codon usage plays an important role in regulating mRNA translation efficiency. We found that the rare codon-dependent premature termination is mediated by the translation termination factor eRF1, which recognizes ribosomes stalled on rare sense codons. Silencing of eRF1 expression resulted in codon usage-dependent changes in protein expression. Together, these results establish a mechanism for how codon usage regulates mRNA translation efficiency.

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