5'-Untranslated regions with multiple upstream AUG codons can support low-level translation via leaky scanning and reinitiation

Wang, Xue‐Qing; Rothnagel, Joseph A.

doi:10.1093/nar/gkh305

Cited by 126 publications

(135 citation statements)

References 41 publications

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“…Abundant evidence supports the role of uORFs as translational regulators, exerting this function through their engagement of ribosomes [61][62][63], inferring this is the main, canonical function of uORFs. Similarly, it has been suggested that smORFs within LncRNAs, or overlapping annotated coding mRNAs, could function mainly as regulators of transcript stability, by engaging the non-sense mediated decay (NMD) pathway [64][65] .…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

New Peptides Under the s(ORF)ace of the Genome

Pueyo

Magny

Couso

2016

Trends in Biochemical Sciences

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Hundreds of previously unidentified functional small peptides could exist in most genomes, but these sequences have been generally overlooked. The discovery of genes encoding small peptides with important functions in different organisms, has ignited the interest in these sequences, and led to an increasing amount of effort towards their identification.Here, we review the advances, both, computational, and biochemical, that are leading the way in the discovery of putatively functional smORFs, as well as the functional studies that have been carried out as a consequence of these searches. The evidence suggests that smORFs form a substantial part of our genomes, and that their encoded peptides could have important functions in a variety of cellular functions.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

New Peptides Under the s(ORF)ace of the Genome

Pueyo

Magny

Couso

2016

Trends in Biochemical Sciences

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“…We have shown that translation at the CFTR pAUG codon occurs at 15% of wildtype levels in the context of the CFTR -132 5´UTR. A number of possible mechanisms could result in the failure of scanning small rRNA subunits to recognise and initiate translation at the c.-34C>T uAUG in the CFTR -132 5´UTR and continue scanning, termed 'leaky' scanning [Wang and Rothnagel, 2004]. Such small rRNA subunits may continue scanning and then recognise the CFTR pAUG and initiate translation of the protein coding sequence.…”

Section: Discussionmentioning

confidence: 99%

Disrupted posttranscriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5′UTR mutation is associated with a cftr-related disease

2011

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Cystic fibrosis (CF) is characterised as a single-gene disorder with a simple, autosomal recessive mode of inheritance. However, translation of CFTR genotype into CF phenotype is influenced by nucleotide sequence variations at multiple genetic loci, and individuals heterozygous for CFTR mutations are predisposed to a range of CFTR-related conditions, such as Disseminated Bronchiectasis. CF disease severity and CFTR-related conditions are more akin to complex, multifactorial traits, which are increasingly being associated with mutations that perturb gene expression. We have identified a patient with Disseminated Bronchiectasis, who is heterozygous for a single nucleotide substitution in the CFTR 5´UTR (c.-34C>T). The c.-34C>T mutation creates an upstream AUG codon and upstream open reading frame that overlaps, and is out of frame with, the CFTR protein coding sequence. Using luciferase reporter constructs, we have shown that the c.-34C>T mutation decreases gene expression by 85%-99%, by reducing translation efficiency and mRNA stability. This is the first CFTR regulatory mutation shown to act at a post-transcriptional level that reduces the synthesis of normal CFTR (Class V), and reaffirms the importance of regulatory mutations as a genetic basis of multifactorial phenotypes.

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“…Upstream AUGs not in frame with the start codon may lead to leaky scanning (Kozak 1989a, b) and reinitiation of translation, resulting in inefficient translation of mRNAs (Wang and Rothnagel 2004). When the first and second start codons are in different reading frames, leaky scanning enables one mRNA to produce two completely different proteins.…”

Section: Start Codon Context Of Rice and Arabidopsis 5-utrsmentioning

confidence: 99%

Genome-wide comparative analysis of Oryza sativa (japonica) and Arabidopsis thaliana 5'-UTR sequences for translational regulatory signals

Shashikanth

Krishna

Ramya

et al. 2008

Plant Biotechnology

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Untranslated regions of eukaryotic genes contain elements that in combination with proteins/RNAs modulate translation of individual messenger RNAs. Elements present in 5Ј-UTRs that influence translational efficiency include AUG sequence context, and presence of uAUGs/uORFs. To assess the level of 5Ј-UTR mediated translational regulation in rice, a genome-wide computational analysis of rice 5Ј-UTRs was carried out in comparison with 5Ј-UTRs of Arabidopsis. Rice 5Ј-UTRs were generally longer and more GC-rich than those of Arabidopsis. 30% of rice and 34% of Arabidopsis cDNAs contained upstream AUG triplets (uAUGs). For both organisms, a higher proportion of uAUG-less cDNAs possessed start codons which conformed to the consensus sequence context compared to uAUG-containing cDNAs. Although the GC composition of the start codon context varied between and within rice and Arabidopsis, the critical positions, ϩ4 and Ϫ3, were conserved. 24% of rice and 30% of Arabidopsis cDNAs possessed upstream open reading frames (uORFs). Combinatorial analyses of start-codon context, uAUG context and context of uAUGs of upstream open reading frames of individual genes indicate that about 30-34% of genes in rice and Arabidopsis are likely to be influenced at translational level by signals present in 5Ј-UTR as they possess uAUG/uORFs with sequence context conforming to the consensus sequence There was very little conservation of uAUG positions or uORFs between rice and Arabidopsis. However, there was conservation of uAUG positions between rice, wheat and barley.

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5'-Untranslated regions with multiple upstream AUG codons can support low-level translation via leaky scanning and reinitiation

Cited by 126 publications

References 41 publications

New Peptides Under the s(ORF)ace of the Genome

New Peptides Under the s(ORF)ace of the Genome

Disrupted posttranscriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5′UTR mutation is associated with a cftr-related disease

Genome-wide comparative analysis of Oryza sativa (japonica) and Arabidopsis thaliana 5'-UTR sequences for translational regulatory signals

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