The regulatory potential of upstream open reading frames in eukaryotic gene expression

Upstream open reading frames (uORFs) are prevalent cis-regulatory sequence elements in the transcript leader sequences (TLSs) of eukaryotic mRNAs. The majority of uORFs is considered to repress downstream translation by the consumption of functional pre-initiation complexes or by inhibiting unrestrained progression of the ribosome. Under distinct conditions, specific uORF properties or sequential arrangements of uORFs can oppositely confer enhanced translation of the main coding sequence, designating uORFs as versatile modifiers of gene expression. Ribosome profiling and proteomic studies demonstrated widespread translational activity at AUG- and non-AUG-initiated uORFs in eukaryotic transcriptomes from yeast to human and several reports linked defective uORF-mediated translational control to the development of human diseases. This review summarizes the structural features affecting uORF-mediated translational control in eukaryotes and describes the highly divergent mechanisms of uORF regulation that result in repression or induction of downstream protein translation.