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

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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. WIREs RNA 2014, 5:765–768. doi: 10.1002/wrna.1245 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions Translation > Translation Regulation
Structural properties affecting the regulatory potential of upstream open reading frames (uORFs). (a) The models depict various structural appearances of uORFs (orange/red bars). Transcript leader sequences (black lines) may contain single or multiple uORFs positioned between the 5′cap structure (black circle) and the CDS (blue bars). Upstream ORFs may be located fully upstream, overlap the CDS initiation codon or may be interlaced between alternative initiation codons within the CDS. Green arrows indicate the two possible ways of CDS translation in the presence of uORFs, i.e., reinitiation and/or leaky scanning. Upstream ORFs may overlap each other in‐ or out‐of‐frame, or appear as a group of multiple individual uORFs. (b) The regulatory function of a uORF is strongly affected by numerous individual features including its length and position within the TLS, the quality of the Kozak consensus sequence surrounding the initiation codon (green line), the composition of the termination context surrounding the upstream stop codon (red line), and by stable secondary structures (black loops) located elsewhere in the messenger RNA (mRNA).
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Mechanistic modes of uORF‐mediated translational control. (a) Simplified model of uORF‐mediated expression regulation of yeast GCN4 in response to stress‐induced depletion of the eIF2–GTP–Met‐tRNAi complex. See main text for a detailed description. The figure uses the same graphical layout as introduced in Figure . (b–e) Graphic representations of ligand‐induced ribosome stalling at peptide‐specific uORFs, of nonsense‐mediated decay induced by ribosome stalling at uORF termination codons, of uORF‐directed start site selection of post‐termination ribosomes, and of uORF‐dependent ribosome shunting across inhibitory secondary structures within the TLS.
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Translation > Translation Regulation
RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions

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