5′‐UTRs and Regulation

Abstract

The 5′‐untranslated region (UTR) consists of the leading part of a cellular messenger ribonucleic acid (mRNA) from the 5′ end to the translation start codon AUG. Precursor mRNA is posttranscriptionally modified by the removal of introns and by the addition at the 5′ end of a 7‐methyl‐guanylate cap structure, which has a crucial role in translation initiation and regulating transcript stability. 5′‐UTRs and 3′‐UTRs are deeply involved in posttranscriptional regulation of gene expression through specific motifs or RNA base modifications that can affect mRNA stability, subcellular localisation, nuclear export, tissue specificity and efficiency of translation.

5‐UTR regulation of translation is modulated by several cis‐acting elements that may also interact with trans acting factors such as proteins or microRNAs. The best studied elements are secondary structures that affect ribosome scanning efficiency (i.e. iron‐responsive element), internal ribosome entry sites (IRESs) and upstream open reading frames (uORFs).

Key Concepts

  • 5′‐UTRs are involved in posttranscriptional regulation of gene expression.
  • Elements located in 5′‐UTRs interfere with ribosome scanning and modulate translation of main AUG.
  • Secondary structures can interfere with ribosome scanning and can be stabilised or destabilised by protein or RNA interaction.
  • Upstream open reading frames (uORFs) may modulate translation efficiency regulating ribosome leaky scanning and translation reinitiation.
  • Alternative spliced mRNAs or usage of alternative TSSs (transcription start sites) may produce transcripts with different 5′‐UTRs modulating translation efficiency.

Keywords: translation initiation; mRNA stability; uAUG; uORF; internal ribosome entry site

Figure 1. mRNAs with alternative 5′‐UTRs can be generated either by the use of alternative promoters, which results in different transcription start sites (TSS1 and TSS2), or by alternative spicing events. In this way, alternative 5′‐UTRs corresponding to the same gene may contain different combinations of regulatory elements, as shown here. CDS, coding sequence; mG7, 7‐methyl‐guanylate; IRES, internal ribosome entry site; sAUG, start AUG; uAUG, upstream AUG and uORF, upstream open reading frame.
Figure 2. Translation initiation regulation. (a) Canonical scanning model; (b) ribosome stalling; (c) inefficient (top) and efficient (bottom) reinitiation, depending on the distance between the uORF and the sAUG; (d) regulation by uORF‐encoded peptide; (e) detachment of the ribosome mediated by an uORF stop codon; (f) IRES‐mediated initiation; (g) inhibition of secondary structure and (h) in‐frame or out‐of‐frame translation starting from an uAUG.
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Further Reading

Barbosa C, Peixeiro I and Romão L (2013) Gene expression regulation by upstream open reading frames and human disease. PLoS Genetics 9: e1003529.

Hellen CU and Sarnow P (2001) Internal ribosome entry sites in eukaryotic mRNA molecules. Genes and Development 15: 1593–1612.

Hinnebusch AG, Ivanov IP and Sonenberg N (2016) Translational control by 5′‐untranslated regions of eukaryotic mRNAs. Science 352 (6292): 1413–1416.

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Vilela C, Ramirez CV, Linz B, Rodrigues‐Pousada C and McCarthy JE (1999) Post‐termination ribosome interactions with the 5′ UTR modulate yeast mRNA stability. EMBO Journal 18: 3139–3152.

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Mignone, Flavio, and Pesole, Graziano(Dec 2016) 5′‐UTRs and Regulation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005010.pub3]