Abstract
Upstream open reading frames (uORFs) are major gene expression regulatory elements. In many eukaryotic mRNAs, one or more uORFs precede the initiation codon of the main coding region. Indeed, several studies have revealed that almost half of human transcripts present uORFs. Very interesting examples have shown that these uORFs can impact gene expression of the downstream main ORF by triggering mRNA decay or by regulating translation. Also, evidence from recent genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of many human diseases, including malignancies, metabolic or neurologic disorders, and inherited syndromes. In this review, we will briefly present the mechanisms through which uORFs regulate gene expression and how they can impact on the organism's response to different cell stress conditions. Then, we will emphasize the importance of these structures by illustrating, with specific examples, how disturbed uORF-mediated translational control can be involved in the etiology of human diseases, giving special importance to genotype-phenotype correlations. Identifying and studying more cases of uORF-altering mutations will help us to understand and establish genotype-phenotype associations, leading to advancements in diagnosis, prognosis, and treatment of many human disorders.
Highlights
Regulation of gene expression at the post-transcriptional level is increasingly being recognized as a key mechanism by which cells and organisms can rapidly change their gene expression patterns in response to internal or external stimuli
Translational regulation at the initiation step can be mediated via different cis-acting elements present in the RNA 59 leader sequence of specific transcripts; these elements include the secondary structure that is able to inhibit AUG initiation codon recognition due to a blockage of the scanning ribosome, internal ribosome entry sites (IRESs) that stimulate cap-independent translation, protein binding sites that either repress or promote translation in response to relaying molecular signals, non-AUG initiation codons, the AUG sequence context that affects efficiency of AUG recognition, and upstream AUG codons, in some cases, associated with upstream open reading frames. uORFs are sequences defined by an initiation codon in frame with a termination codon located upstream or downstream of the main
This study showed that these uORFs induce a 30–60% decrease in protein levels when compared to the protein levels expressed from the corresponding allele without the uORF-altering single nucleotide polymorphisms (SNPs) variant [2]
Summary
Regulation of gene expression at the post-transcriptional level is increasingly being recognized as a key mechanism by which cells and organisms can rapidly change their gene expression patterns in response to internal or external stimuli. In conditions of reduced ternary complex availability, initiation of the second uORF is less likely, as there is less chance of the scanning ribosomal subunit recruiting the ternary complex required for start codon recognition [63,64] (Figure 2) By this mechanism, a reduction in active eIF2 induces increased protein expression from mRNAs carrying the correct arrangement of uORFs (Figure 1G and Figure 1H) [65,66]. The examples shown here suggest that the translational control mediated by uORFs may involve several steps of mRNA metabolism, may include unfolding of mRNA structures, specific sequences, or trans-acting factors, may occur in a context-dependent manner, and may respond differently to stress-activated translation initiation factors. It was demonstrated that this protein reduction is due to the
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