Mitotic checkpoint gene expression is tuned by codon usage bias
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ABSTRACT:
SUBMITTER: Mr. Eric Esposito
PROVIDER: S-SCDT-EMBOJ-2021-107896 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:The mitotic checkpoint (also called spindle assembly checkpoint, SAC) is a signaling pathway that safeguards proper chromosome segregation. Correct functioning of the SAC depends on adequate protein concentrations and appropriate stoichiometries between SAC proteins. Yet very little is known about the regulation of SAC gene expression. Here, we show in the fission yeast Schizosaccharomyces pombe that a combination of short mRNA half-lives and long protein half-lives supports stable SAC protein levels. For the SAC genes mad2+ and mad3+ , their short mRNA half-lives are caused, in part, by a high frequency of nonoptimal codons. In contrast, mad1+ mRNA has a short half-life despite a higher frequency of optimal codons, and despite the lack of known RNA-destabilizing motifs. Hence, different SAC genes employ different strategies of expression. We further show that Mad1 homodimers form co-translationally, which may necessitate a certain codon usage pattern. Taken together, we propose that the codon usage of SAC genes is fine-tuned to ensure proper SAC function. Our work shines light on gene expression features that promote spindle assembly checkpoint function and suggests that synonymous mutations may weaken the checkpoint.
| S-EPMC9340482 | biostudies-literature
Project description:Codon usage bias is the preferential or non-random use of synonymous codons, a ubiquitous phenomenon observed in bacteria, plants and animals. Different species have consistent and characteristic codon biases. Codon bias varies not only with species, family or group within kingdom, but also between the genes within an organism. Codon usage bias has evolved through mutation, natural selection, and genetic drift in various organisms. Genome composition, GC content, expression level and length of genes, position and context of codons in the genes, recombination rates, mRNA folding, and tRNA abundance and interactions are some factors influencing codon bias. The factors shaping codon bias may also be involved in evolution of the universal genetic code. Codon-usage bias is critical factor determining gene expression and cellular function by influencing diverse processes such as RNA processing, protein translation and protein folding. Codon usage bias reflects the origin, mutation patterns and evolution of the species or genes. Investigations of codon bias patterns in genomes can reveal phylogenetic relationships between organisms, horizontal gene transfers, molecular evolution of genes and identify selective forces that drive their evolution. Most important application of codon bias analysis is in the design of transgenes, to increase gene expression levels through codon optimization, for development of transgenic crops. The review gives an overview of deviations of genetic code, factors influencing codon usage or bias, codon usage bias of nuclear and organellar genes, computational methods to determine codon usage and the significance as well as applications of codon usage analysis in biological research, with emphasis on plants.
| S-EPMC8613526 | biostudies-literature
Project description:BackgroundProtein synthesis is one of the extremely important anabolic pathways in the yeast expression system Pichia pastoris. Codon optimization is a commonly adopted strategy for improved protein expression, although unexpected failures did appear sometimes waiting for further exploration. Recently codon bias has been studied to regulate protein folding and activity in many other organisms.ResultsHere the codon bias profile of P. pastoris genome was examined first and a direct correlation between codon translation efficiency and usage frequency was identified. By manipulating the codon choices of both endogenous and heterologous signal peptides, secretion abilities of N-terminal signal peptides were shown to be tolerant towards codon changes. Then two gene candidates with different levels of structural disorder were studied, and full-length codon optimization was found to affect their expression profiles differentially. Finally, more evidences were provided to support possible protein conformation change brought by codon optimization in structurally disordered proteins.ConclusionOur results suggest that codon bias regulates gene expression by modulating several factors including transcription and translation efficiency, protein folding and activity. Because of sequences difference, the extent of affection may be gene specific. For some genes, special codon optimization strategy should be adopted to ensure appropriate expression and conformation.
| S-EPMC8077831 | biostudies-literature
Project description:Codon usage is biased between lowly and highly expressed genes in a genome-specific manner. This universal bias has been well assessed in some unicellular species, but remains problematic to assess in more complex species. We propose a new method to compute codon usage bias based on genome wide translational data. A new technique based on sequencing of ribosome protected mRNA fragments (Ribo-seq) allowed us to rank genes and compute codon usage bias with high precision for a great variety of species, including mammals. Genes ranking using Ribo-Seq data confirms the influence of the tRNA pool on codon usage bias and shows a decreasing bias in multicellular species. Ribo-Seq analysis also makes possible to detect preferred codons without information on genes function.
| S-EPMC5499818 | biostudies-literature
Project description:Although the mapping of codon to amino acid is conserved across nearly all species, the frequency at which synonymous codons are used varies both between organisms and between genes from the same organism. This variation affects diverse cellular processes including protein expression, regulation, and folding. Here, we mathematically model an additional layer of complexity and show that individual codon usage biases follow a position-dependent exponential decay model with unique parameter fits for each codon. We use this methodology to perform an in-depth analysis on codon usage bias in the model organism Escherichia coli. Our methodology shows that lowly and highly expressed genes are more similar in their codon usage patterns in the 5'-gene regions, but that these preferences diverge at distal sites resulting in greater positional dependency (pD, which we mathematically define later) for highly expressed genes. We show that position-dependent codon usage bias is partially explained by the structural requirements of mRNAs that results in increased usage of A/T rich codons shortly after the gene start. However, we also show that the pD of 4- and 6-fold degenerate codons is partially related to the gene copy number of cognate-tRNAs supporting existing hypotheses that posit benefits to a region of slow translation in the beginning of coding sequences. Lastly, we demonstrate that viewing codon usage bias through a position-dependent framework has practical utility by improving accuracy of gene expression prediction when incorporating positional dependencies into the Codon Adaptation Index model.
| S-EPMC4069614 | biostudies-literature
Project description:BackgroundSynonymous codons are used differentially in organisms from the three domains of life, a phenomenon referred to as codon usage bias. In addition, codon pair bias, particularly in the 3' codon context, has also been described in several organisms and is associated with the accuracy and rate of translation. An improved understanding of both types of bias is important for the optimization of heterologous protein expression, particularly in biotechnologically important organisms, such as the yeast Xanthophyllomyces dendrorhous, a promising bioresource for the carotenoid astaxanthin. Using genomic and transcriptomic data, the codon usage and codon context biases of X. dendrorhous open reading frames (ORFs) were analyzed to determine their expression levels, GC% and sequence lengths. X. dendrorhous totiviral ORFs were also included in these analyses.ResultsA total of 1,695 X. dendrorhous ORFs were identified through comparison with sequences in multiple databases, and the intron-exon structures of these sequences were determined. Although there were important expression variations among the ORFs under the studied conditions (different phases of growth and available carbon sources), most of these sequences were highly expressed under at least one of the analyzed conditions. Independent of the culture conditions, the highly expressed genes showed a strong bias in both codon usage and the 3' context, with a minor association with the GC% and no relationship to the sequence length. The codon usage and codon-pair bias of the totiviral ORFs were highly variable with no similarities to the host ORFs.ConclusionsThere is a direct relation between the level of gene expression and codon usage and 3' context bias in X. dendrorhous, which is more evident for ORFs that are expressed at the highest levels under the studied conditions. However, there is no direct relation between the totiviral ORF biases and the host ORFs.
| S-EPMC4404019 | biostudies-literature
Project description:Positive correlation between gene expression and synonymous codon usage bias is well documented in the literature. However, in the present study of Vibrio cholerae genome, we have identified a group of genes having unusually high codon usage bias despite being low potential expressivity. Our results suggest that codon usage in lowly expressed genes might also be selected on to preferably use non-optimal codons to maintain a low cellular concentration of the proteins that they encode. This would predict that lowly expressed genes are also biased in codon usage, but in a way that is opposite to the bias of highly expressed genes.
| S-EPMC2646191 | biostudies-literature
Project description:Codon usage bias (CUB) has been described in viruses, prokaryotes, and eukaryotes and has been linked to several cellular and environmental factors, such as the organism's growth temperature, gene expression levels, and regulation of protein synthesis and folding. Most of the studies in this area have been conducted in bacteria and higher eukaryotes, in some cases with different results. In this study, a comparative analysis of CUB in yeasts isolated from cold and template environments was performed in order to evaluate the correlation of CUB with yeast optimal temperature of growth (OTG), gene expression levels, cellular function, and structure of encoded proteins. Among the main findings, highly expressed ORFs tend to have a more similar CUB within and between yeasts, and a direct correlation between codons ending in C and expression level was generally found. A low correspondence between CUB and OTG was observed, with an inverse correlation for some codons ending in C. The clustering of yeasts based on their CUB partially aligns with their OTG, being more consistent for yeasts with lower OTG. In most yeasts, the abundance of preferred codons was generally lower at the 5' end of ORFs, higher in segments encoding beta strand, lower in segments encoding extracellular and transmembrane regions, and higher in "translation" and "energy metabolism" pathways, especially in highly expressed ORFs. Based on our findings, it is suggested that the abundance and distribution of preferred and non-preferred codons along mRNAs contribute to proper protein folding and functionality by regulating protein synthesis rates, becoming a more important factor under conditions that require faster protein synthesis in yeasts.
| S-EPMC11260810 | biostudies-literature
Project description:Differences in codon frequency between genomes, genes, or positions along a gene, modulate transcription and translation efficiency, leading to phenotypic and functional differences. Here, we present a multiscale analysis of the effects of synonymous codon recoding during heterologous gene expression in human cells, quantifying the phenotypic consequences of codon usage bias at different molecular and cellular levels, with an emphasis on translation elongation. Six synonymous versions of an antibiotic resistance gene were generated, fused to a fluorescent reporter, and independently expressed in HEK293 cells. Multiscale phenotype was analyzed by means of quantitative transcriptome and proteome assessment, as proxies for gene expression; cellular fluorescence, as a proxy for single-cell level expression; and real-time cell proliferation in absence or presence of antibiotic, as a proxy for the cell fitness. We show that differences in codon usage bias strongly impact the molecular and cellular phenotype: (i) they result in large differences in mRNA levels and protein levels, leading to differences of over 15 times in translation efficiency; (ii) they introduce unpredicted splicing events; (iii) they lead to reproducible phenotypic heterogeneity; and (iv) they lead to a trade-off between the benefit of antibiotic resistance and the burden of heterologous expression. In human cells in culture, codon usage bias modulates gene expression by modifying mRNA availability and suitability for translation, leading to differences in protein levels and eventually eliciting functional phenotypic changes.
| S-EPMC9926478 | biostudies-literature
Project description:The rate of protein synthesis depends on both the rate of initiation of translation and the rate of elongation of the peptide chain. The rate of initiation depends on the encountering rate between ribosomes and mRNA; this rate in turn depends on the concentration of ribosomes and mRNA. Thus, patterns of codon usage that increase transcriptional efficiency should increase mRNA concentration, which in turn would increase the initiation rate and the rate of protein synthesis. An optimality model of the transcriptional process is presented with the prediction that the most frequently used ribonucleotide at the third codon sites in mRNA molecules should be the same as the most abundant ribonucleotide at the third codon sites in mRNA molecules should be the same as the most abundant ribonucleotide in the cellular matrix where mRNA is transcribed. This prediction is supported by four kinds of evidence. First, A-ending codons are the most frequently used synonymous codons in mitochondria, where ATP is much more abundant than that of the three other ribonucleotides. Second, A-ending codons are more frequently used in mitochondrial genes than in nuclear genes. Third, protein genes from organisms with a high metabolic rate use more A-ending codons and have higher A content in their introns than those from organisms with a low metabolic rate.
| S-EPMC1207621 | biostudies-other