Cost minimization of ribosomal frameshifts

J Theor Biol. 2007 Nov 7;249(1):162-7. doi: 10.1016/j.jtbi.2007.07.007. Epub 2007 Jul 18.

Abstract

Properties of mRNA leading regions that modulate protein synthesis are little known (besides effects of their secondary structure). Here I explore how coding properties of leading regions may account for their disparate efficiencies. Trinucleotides that form off frame stop codons decrease costs of ribosomal slippages during protein synthesis: protein activity (as a proxy of gene expression, and as measured in experiments using artificial variants of 5' leading sequences of beta galactosidase in Escherichia coli) increases proportionally to the number of stop motifs in any frame in the 5' leading region. This suggests that stop codons in the 5' leading region, upstream of the recognized coding sequence, terminate eventual translations that sometimes start before ribosomes reach the mRNA's recognized start codon, increasing efficiency. This hypothesis is confirmed by further analyses: mRNAs with 5' leading regions containing in the same frame a start preceding a stop codon (in any frame) produce less enzymatic activity than those with the stop preceding the start. Hence coding properties, in addition to other properties, such as the secondary structure of the 5' leading region, regulate translation. This experimentally (a) confirms that within coding regions, off frame stops increase protein synthesis efficiency by early stopping frameshifted translation; (b) suggests that this occurs for all frames also in 5' leading regions and that (c) several alternative start codons that function at different probabilities should routinely be considered for all genes in the region of the recognized initiation codon. An unknown number of short peptides might be translated from coding and non-coding regions of RNAs.

MeSH terms

  • 5' Untranslated Regions
  • Alternative Splicing
  • Animals
  • Codon
  • Frameshifting, Ribosomal*
  • Gene Expression Regulation*
  • Genetic Variation
  • Models, Genetic*
  • Protein Biosynthesis / genetics
  • Regulatory Sequences, Ribonucleic Acid

Substances

  • 5' Untranslated Regions
  • Codon
  • Regulatory Sequences, Ribonucleic Acid