NonAUG

NonAUG refers to translation initiation at codons other than the canonical AUG start codon. In many organisms, initiation can occur at near-cognate codons such as CUG, GUG, and UUG, though with lower efficiency than AUG. NonAUG initiation expands proteome diversity by producing alternative protein isoforms or N-terminal extensions from the same mRNA.

Mechanistically, start codon selection depends on scanning by the 43S preinitiation complex, the availability of the initiator tRNA and initiation factors, and the sequence context surrounding the codon. In eukaryotes, the surrounding Kozak context, as well as the structure of the 5' untranslated region, influence whether a near-cognate codon is used. The activity of initiation factors that govern start-site stringency, notably eIF1 and eIF5, also shapes the balance between AUG and non-AUG initiation.

NonAUG translation is biologically significant because it can contribute to tissue- or condition-specific protein repertoires and to regulatory layers in gene expression. It has been observed across diverse organisms and is increasingly documented through ribosome profiling and mass spectrometry, which reveal widespread but gene- and context-dependent non-AUG initiation events. In some cases, non-AUG starts produce functional protein isoforms with distinct N-termini that alter localization, stability, or activity.

Detection methods include ribosome profiling, comparative reporter assays, and targeted proteomics. Regulation of non-AUG initiation is multifactorial, involving the cellular context, mRNA features, and the availability and activity of initiation factors that determine start codon stringency.