1. Upstream open reading frames (uORFs) in eukaryotic mRNAs

uORFs are small ORFs located in the 5′ untranslated regions (5'UTRs) of many eukaryotic mRNAs (Fig. 1). Recent genome-wide analyses revealed that 10%?50% of eukaryotic genes contain at least one uORF. Since the ribosomes of eukaryotes scan mRNAs from their 5′ ends, the presence of a uORF can negatively modulate the translational efficiency of the main ORF downstream. Regulatory roles of uORFs have been demonstrated in processes such as stress responses and feedback regulation of biosynthesis. While the effects of most uORFs seem to be independent of their amino acid sequence, several uORFs affect the translation of the main ORF in an amino acid sequence-dependent manner. For example, in translational feedback regulation of the Neurospora crassa arg-2 gene, which encodes the small subunit of arginine-specific carbamoyl phosphate synthetase, the 24-residue nascent peptide encoded by the arg-2 uORF causes ribosome stalling at the stop codon of the uORF in response to arginine. The stalled ribosome, in turn, prevents other scanning ribosomes from reaching the initiation codon of the main ORF, resulting in translational inhibition of the main ORF (Fig. 1).