Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease


Upstream open reading frames (uORFs) are cis‐acting elements, located before or overlapped with the main coding ORF (mORF), that regulate cap‐dependent translation efficiency in a transcript‐specific manner. More than half of the human transcripts bear at least one uORF. In addition, it has been recently revealed that many of these uORFs initiate at non‐AUG codons, which significantly increases the complexity and diversity of the human translatome. These regulons are considered repressors of downstream translation but, in some biological contexts, they induce mORF expression. There are several the mechanisms by which AUG and non‐AUG uORFs regulate gene expression, allowing the cell to control transcript‐specific translation according to its needs. Also, we describe several examples of uORF genetic variants associated with human genetic diseases. Studying these cases and understanding the resultant abnormal mechanisms of uORF‐mediated translational control is of extreme importance for the development of new therapeutic strategies.

Key Concepts

  • Upstream open reading frames (uORFs) are cis‐acting translational regulatory elements present within the 5′ leader sequence of mRNAs.
  • uORFs can regulate gene expression by repressing or promoting translation of the downstream main ORF (mORF), according to the cellular environment.
  • The number of uORFs, the intercistronic distance, the overlap with the mORF and the context of the initiation codon are the uORF‐related structural features that most influence their translational regulatory capacity.
  • uORF‐mediated repression of mORF translation is usually achieved by ribosome dissociation, ribosome stalling, induction of nonsense‐mediated mRNA decay (NMD) or production of inhibitory peptides.
  • uORF‐mediated induction of mORF translation is usually achieved by ribosome bypass or translation reinitiation.
  • uORFs initiated by non‐AUG codons are more frequent than previously appreciated, having important biological functions.
  • uORF‐altering polymorphisms and mutations, which create, disrupt or change a uORF, can cause human genetic diseases.
  • Studying and understanding the uORF‐mediated mechanisms of gene expression regulation may provide knowledge to develop novel therapies for several human diseases.

Keywords: gene expression regulation; mRNA translation; translational control; upstream open reading frame (uORF); non‐AUG‐uORF; stress

Figure 1. Model of the canonical eukaryotic translation initiation process. The process begins with the assembly of the 43S PIC, with eIFs 1A, 1, 3 and 5 binding initially and stimulating recruitment of the TC, composed of eIF2, GTP and Met‐tRNAiMet. The 43S PIC attaches near the 5′ cap of the mRNA through interaction of eIF3 and eIF4G, which is part of the eIF4F complex (eIFs 4G, 4E and 4A), forming a 48S‐activated mRNA. The subsequent scanning of the mRNA from 5′ to 3′ is accompanied by GTP hydrolysis by the TC without releasing Pi. Base‐pairing between the start codon and the anti‐codon of the tRNAiMet at the P‐site promotes conformational changes within the PIC, with the consequent release of Pi, eIF1, and eIF2‐GDP in complex with eIF5. Then, eIF5B bound to GTP promotes joining of the 60S subunit, with release of eIF5B‐GDP and eIF1A to form the 80S ribosome, ready to continue with the elongation phase. The released eIF2‐GDP is then recycled to eIF2‐GTP by the exchange factor, eIF2B, to start a new round of translation initiation.
Figure 2. Ribosome stalling/dissociation at uORFs inhibits translation of CHOP and GADD34 mORFs. (a) During basal conditions, ribosomes initiate translation at CHOP uORF. Translation of an Ile‐Phe‐Ile sequence promotes ribosome stalling and prevents translation of CHOP mORF, causing low levels of CHOP expression. (b) During basal conditions, scanning ribosomes bypass the GADD34 uORF1 due to its poor start codon context and initiate translation at uORF2. Translation of a Pro‐Pro‐Gly peptide sequence juxtaposed to the uORF2 stop codon results in ribosome dissociation from the mRNA and causes low levels of GADD34 expression.
Figure 3. uORF‐mediated control of ATF4 expression in basal and stress conditions. (a) During normal conditions, ribosomes scanning the ATF4 mRNA initiate translation at uORF1. After termination, the 40S ribosomal subunits quickly reacquire a new ternary complex and reinitiate translation at uORF2, which overlaps out‐of‐frame with ATF4 mORF. Translation of uORF2 results in ribosome termination 3′ of the ATF4 initiation codon, which inhibits mORF translation. At the same time, the uORF2 stop codon is recognised as a premature termination codon (PTC), activating the NMD machinery that leads to mRNA decay. Altogether, these mechanisms contribute to low basal ATF4 expression at both protein and mRNA levels. (b) Elevated eIF2α‐P during stress conditions results in low ternary complex availability. Thus, after the translation of ATF4 uORF1, the post‐translation 40S ribosomal subunit scans through the inhibitory uORF2, reacquiring a new ternary complex in time to initiate translation at the ATF4 mORF. This mechanism of ‘delayed reinitiation’ allows the expression of ATF4 during cellular stress.
Figure 4. uORF‐mediated translation of GADD34 and CHOP mORFs during stress. (a) During stress conditions, elevated eIF2α‐P results in ribosomal bypass of GADD34 uORF1 and uORF2 due to their weak/moderate start codon contexts. Bypass of the inhibitory uORF2 results in increased translation initiation at the GADD34 mORF to promote GADD34 expression. (b) Increased eIF2α‐P during stress also promotes bypass of the inhibitory uORF of CHOP due to its weak start codon context, allowing translation initiation at the CHOP mORF to increase its expression.
Figure 5. Mechanistic and structural aspects that determine non‐AUG‐uORF recognition and their regulatory potential. (a) Different eIFs can contribute to non‐AUG start codon recognition during translation initiation. The eIF2 delivers the canonical Met (M)‐tRNAiMet for translation initiation at a non‐AUG codon in a GTP‐dependent manner, but with low efficiency (grey arrow). Alternatively, eIF2A and eIF2D can deliver the Met‐tRNAiMet or Leu (L)‐tRNA and Val (V)‐tRNA, respectively, to the non‐AUG codon, independently of GTP and with a higher efficiency (black arrows). (b) The abundance of specific eIFs can determine non‐AUG recognition during translation initiation. While increased levels of eIF2A, eIF2α‐P and eIF5 favour translation initiation at non‐AUG codons, high levels of eIF1 or eIF5‐mimic protein (5MP) increase the stringency of start codon selection. (c) The Kozak sequence context (in orange) of the non‐AUG codon can influence its recognition efficiency during translation initiation, as it does for AUG codons. (d) Formation of secondary structures, such as hairpins, downstream of a non‐AUG codon may momentarily pause or slow down the scanning 40S ribosome, providing time for recognition of the non‐optimal start codon and initiate translation.


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Further Reading

Gebauer F and Hentze M (2004) Molecular mechanisms of translational control. Nature Reviews Molecular Cell Biology 5 (10): 827–835.

Jackson R, Hellen C and Pestova T (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nature Reviews Molecular Cell Biology 11 (2): 113–127.

Leppek K, Das R and Barna M (2018) Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nature Reviews Molecular Cell Biology 19 (3): 158–174.

Sonenberg N and Hinnebusch A (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136 (4): 731–745.

Wethmar K (2014) The regulatory potential of upstream open reading frames in eukaryotic gene expression. Wiley interdisciplinary reviews RNA 5 (6): 765–778.

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Fernandes, Rafael, and Romão, Luísa(Sep 2020) Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0029194]