Hidden coding potential of eukaryotic genomes: nonAUG started ORFs

Abstract

It is widely considered that the vast majority of eukaryotic mRNAs contain only one open reading frame (ORF) and encode single protein. However, eukaryotic ribosomes can initiate translation at alternative start codons due to leaky scanning or reinitiation mechanisms that provides an opportunity to synthesize several protein products. Recent investigations also demonstrated that alternative translation from nonAUG start codons and AUG codons in a weak nucleotide context could make an important contribution to eukaryotic proteomes. However, accurate prediction of alternative start codons demands detailed investigation of mRNA features influencing their recognition by eukaryotic ribosomes. In this work, we present the results of computational analysis of characteristics of yeast and mammalian mRNAs potentially involved in the recognition of nonAUG start codons. It was found that sequence features of nonAUG started Saccharomyces cerevisiae upstream ORFs (uORFs) were adjusted for efficient translation and these uORFs could frequently encode functional polypeptides. In particular, our initial studies revealed that predicted tertiary structures downstream of nonAUG start sites in mammalian mRNAs were energetically more stable than those predicted for AUG start sites with strong Kozak context. We hypothesize that presence of such stable tertiary structure downstream of nonAUG start sites could be an important factor for the ribosome to recognize noncanonical start codons.