Abstract
Codon usage bias (the preferential use of certain synonymous codons (optimal) over others is found at the organism level (intergenomic) within specific genomes (intragenomic) and even in certain genes. Whether it is the result of genetic drift due to GC/AT content and/or natural selection is a topic of intense debate. Preferential codons are mostly found in genes encoding highly-expressed proteins, while lowly-expressed proteins usually contain a high proportion of rare (lowly-represented) codons. While optimal codons are decoded by highly expressed tRNAs, rare codons are usually decoded by lowly-represented tRNAs. Whether rare codons play a role in controlling the expression of lowly- or temporarily-expressed proteins is an open question. In this work we approached this question using two strategies, either by replacing rare glycine codons with optimal counterparts in the gene that encodes the cell cycle protein Cdc13, or by overexpression the tRNAGly that decodes rare codons from the fission yeast, Schizosaccharomyces pombe. While the replacement of synonymous codons severely affected cell growth, increasing tRNA levels affected the aggregation status of Cdc13 and cell division. These lead us to think that rare codons in lowly-expressed cyclin proteins are crucial for cell division, and that the overexpression of tRNA that decodes rare codons affects the expression of proteins containing these rare codons. These codons may be the result of the natural selection of codons in genes that encode lowly-expressed proteins.
Highlights
Degeneracy or redundancy of the genetic code implies that more than one codon (2, 4 or 6 codons) exist for 18 of the 20 genetically encoded amino acids
CUB may optimize or deoptimize translation for a group of related mRNAs, coordinating their expression. These interpretations are controversial since some researchers have established that codon usage is an important factor in protein expression in trypanosomatids (Jeacock et al, 2018), where protein concentration can be estimated from protein coding sequences, while in other studies it has been determined that translation elongation speed is independent of codon usage bias (Ingolia et al, 2011)
Translation efficiency and accuracy are largely achieved by binding to the ribosome of the proper aminoacyl-tRNA that tRNA Levels and Cyclin Aggregation compared to controls. (D) Relative levels of cdc13 mRNA compared to those of controls. (*p < 0.05, t-student)
Summary
Degeneracy or redundancy of the genetic code implies that more than one codon (2, 4 or 6 codons) exist for 18 of the 20 genetically encoded amino acids. Experimental evidence and genome-wide analyses suggest that regions between protein domains are enriched in non-optimal codons, while structured domains are mostly encoded by optimal codons (Zhou et al, 2015) Despite these data, it is difficult to predict the synonymous mutations that lead to abnormal protein expression, folding, or function and the response of cells to these defects. The variable levels of tRNAs during the cell cycle (FrenkelMorgenstern et al, 2012) may control the expression of cdc13 To test this hypothesis, we followed two approaches: (1) to introduce synonymous mutations to replace non-optimal with optimal codons in cdc, and (2), to modify the concentration of tRNAs that decode non-optimal codons. Our results show that these alterations significantly affect both Cdc distribution in soluble and aggregated fractions and cell duplication
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