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Translational regulation by upstream open reading frames and its relevance to human genetic disease

2020-09-30Book part Restricted access
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dc.contributor.authorFernandes, Rafael
dc.contributor.authorRomão, Luísa
dc.date.accessioned2021-03-18T11:27:20Z
dc.date.available2021-03-18T11:27:20Z
dc.date.issued2020-09-30
dc.descriptionBased in part on the previous version of this eLS article “ Upstream Open Reading Frames and Human Genetic Disease” (2014) by Cristina Barbosa, Cláudia Onofre and Luísa Romão.pt_PT
dc.description.abstractUpstream 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.pt_PT
dc.description.abstractKey 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationeLS. 2020 Sep 30;1(2). doi: 10.1002/9780470015902.a0029194pt_PT
dc.identifier.doi10.1002/9780470015902.a0029194pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7532
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherJohn Wiley & Sons, Ltd.pt_PT
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/full/10.1002/9780470015902.a0029194pt_PT
dc.subjectGene Expression Regulationpt_PT
dc.subjectmRNA Translationpt_PT
dc.subjectTranslational Controlpt_PT
dc.subjectUpstream Open Reading Frame (uORF)pt_PT
dc.subjectnon‐AUG‐uORFpt_PT
dc.subjectStresspt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleTranslational regulation by upstream open reading frames and its relevance to human genetic diseasept_PT
dc.typebook part
dspace.entity.typePublication
oaire.citation.issue2pt_PT
oaire.citation.titleEncyclopedia of Life Sciences (ELS)pt_PT
oaire.citation.volume1pt_PT
rcaap.embargofctAcesso de acordo com página web do editor da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typebookPartpt_PT

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