The codon composition of the coding sequence’s (ORF) 5′ end first

The codon composition of the coding sequence’s (ORF) 5′ end first few dozen codons is known to be distinct to that of the rest of the ORF. referred to the genes’ promoter (which primarily determines the transcription initiation rates) as the main ‘module’ including information regarding gene expression regulation while the information related to protein structure is contained in the coding sequence via the genetic code. However various studies have demonstrated that such PHT-427 a modularity is only a raw approximation of the reality. The genetic code is redundant as it includes 61 codons that encode only 20 amino acids; thus a certain protein can be encoded by a large (exponential) number of codon combinations. Indeed in recent years it was demonstrated that multiple ‘overlapping codes’ tend to appear in the coding sequence related to all stages of gene expression regulation (1-7): for example replacing a codon with a synonymous one can significantly affect the level of transcript expression. There are some excellent reviews regarding the way information encoded in synonymous codons affects the organismal fitness resulting in a pattern of non-neutral evolution (8-13). The topic of this review however is related only to the 5′ end of the ORF (open reading frame also referred to as coding sequence or CDS). Specifically we will discuss only signals that appear in the first 50-70 codons of the ORF. It has been known for over two decades that the codon frequency distribution at the ORF’s 5′ end PHT-427 is different to that observed in the rest of the ORF (14-17). However only recently have several novel mechanisms been discovered by which the unusual codon usage bias in this region affects gene translation regulation and organismal fitness. The current Rabbit Polyclonal to CSTL1. limitations of the experimental approaches for monitoring the regulation of gene translation added to the fact that this relatively short region is highly occupied with signals related to this process make the research of this part of the sequence challenging. In the current paper we review the different signals that appear in this region the theories related to the way PHT-427 they regulate translation and affect organismal fitness and the controversies related to some of these signals. WEAK FOLDING AT THE 5′ END It was suggested that in the three domains of life bacteria archaea and eukaryotes the first 30-40 nucleotides of the ORF undergo evolutionary selection such that there will be weak folding of the mRNA molecule in the region surrounding the start codon (18-24) as the presence of secondary structures inhibits the ability of an mRNA to sequester PHT-427 ribosomes thereby lowering the effective translation initiation rate. This signal probably promotes efficient recognition of the start codon and the regulatory sequences surrounding it by the pre-initiation complex/30S subunits. If the relevant regulatory sequences Shine-Dalgarno in prokaryotes (25) and start codon context (usually termed Kozak sequence) in eukaryotes (26 27 and the start codon itself tend to be base-paired to other nucleotides they do not interact efficiently with the pre-initiation complex/30S subunits (21) (Figure ?(Figure1A1A). Figure 1. The effect of mRNA folding on translation. All sub-figures include illustrations of the mRNA structure (black) and the ribosomal small and large subunits (green). (A) Illustration of how weak mRNA folding at the 5′ end promotes PHT-427 recognition of … Currently five studies have demonstrated that indeed there is a causal relation between folding at the 5′ end of the ORF and translation efficiency (protein levels) in (18 19 28 and in (29 30 They generated libraries of variants that code the same protein with each variant being comprised of different synonymous codons (specifically at the beginning of the ORF); and the protein level of each variant was measured. Next for each variant the folding strength at the 5′ end was computed and the strength of this folding was found to be negatively correlated with the measured protein levels. It is important to mention however that such a correlation was not observed in a sixth study which analyzed two different reporter PHT-427 genes (31). This shows that the strength of the proposed association between folding at the 5′ end of the ORF and translation efficiency varies among genes and may even vary among different cellular conditions. Specifically if factors such as amino.