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Conserved Upstream Open Reading Frame Nascent Peptides That Control Translation - PubMed

  • ️Wed Jan 01 2020

Review

Conserved Upstream Open Reading Frame Nascent Peptides That Control Translation

Thomas E Dever et al. Annu Rev Genet. 2020.

Abstract

Cells utilize transcriptional and posttranscriptional mechanisms to alter gene expression in response to environmental cues. Gene-specific controls, including changing the translation of specific messenger RNAs (mRNAs), provide a rapid means to respond precisely to different conditions. Upstream open reading frames (uORFs) are known to control the translation of mRNAs. Recent studies in bacteria and eukaryotes have revealed the functions of evolutionarily conserved uORF-encoded peptides. Some of these uORF-encoded nascent peptides enable responses to specific metabolites to modulate the translation of their mRNAs by stalling ribosomes and through ribosome stalling may also modulate the level of their mRNAs. In this review, we highlight several examples of conserved uORF nascent peptides that stall ribosomes to regulate gene expression in response to specific metabolites in bacteria, fungi, mammals, and plants.

Keywords: nascent peptide; protein synthesis; ribosome; translation stalling; uCC; uORF.

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Figures

Figure 1.
Figure 1.. uORF-mediated control of bacterial gene expression.

Transcriptional Off: Rho-dependent termination of transcription in the mRNA 5’-leader occurs when Rho has access to its binding site in the RNA (rut site) as occurs when there is no uORF-mediated ribosome stalling. RNA polymerase pauses at a GC-rich stem structure; if Rho binds to the RNA and by moving 5’ to 3’ on the mRNA catches up to the paused RNA polymerase, transcription will terminate in the 5’-leader. On: Ribosome stalling on the uORF blocks access of Rho to the rut site. RNA polymerase is not impacted by Rho and, therefore, can resume transcription of the downstream protein-coding regions after pausing. Translational Off: Elements (SD, Shine-Dalgarno region) important for downstream translation initiation are masked in RNA secondary structure as occurs when there is no uORF-mediated ribosome stalling. On: Ribosome stalling on the uORF changes RNA secondary structure to unmask the SD and enable downstream translation initiation.

Figure 2.
Figure 2.. uORF-mediated translational control in eukaryotes.

Translation initiation in eukaryotes begins with the small (40S) ribosomal subunit binding near the cap of the mRNA. The ribosome then scans the mRNA (1) inspecting for a start codon. The scanning ribosome either (2) skips over the start codon of the uORF without initiating (leaky scanning) and then translates the mORF or (3) translates the uORF. Multiple possible consequences of uORF translation include: (4) disengagement of the ribosome from the mRNA following translation of a long uORF (mORF translation is repressed) or (5) resumption of scanning by the small ribosomal subunit following translation of a short uORF enables reinitiation of translation at the mORF. If the peptide sequence encoded by the uORF causes ribosomes to pause (or stall) during elongation (6) or termination (7), a short uORF can inhibit mORF translation like a long uORF. Both the elongation and termination pausing events can prevent subsequent ribosomes from leaky scanning (8) to the mORF, and in some cases via ribosome queuing promote initiation at the uORF start codon (9) to create a positive feedback loop that enhances uORF translation and represses mORF translation.

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