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Gene expression regulation by upstream open reading frames and human disease
Barbosa, Cristina; Peixeiro, Isabel; Romão, LuísaUpstream 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 ...
Nonsense-mediated decay resistance of AUG-proximal nonsense-mutated transcripts...
Peixeiro, Isabel; Barbosa, Cristina; Romão, LuísaApresentação oral por convite. ; Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and rapidly degrades mRNAs containing a premature termination codon (PTC). The unified model for NMD proposes that the decision of NMD triggering is the outcome of the competition between the cytoplasmatic poly(A)-binding protein 1 (PABPC1) and the NMD effector UPF1 for the termination complex. Consequ...
Assessing the involvement of Dis3L1 in mammalian quality control pathways
Reis, Filipa Pereira; Teixeira, Alexandre; Cruz, David; Morgado, Ana; Arraiano, Cecília Maria; Romão, LuísaThe exosome is an evolutionarily conserved protein complex that is involved in all aspects of RNA metabolism, namely, RNA decay, processing and quality control. The only catalytic subunit of the core exosome is a 3´end exoribonuclease from the RNase II family of enzymes. In humans, two different homologues of this protein were identified, Dis3 and Dis3L1. While Dis3 mainly localizes in the nucleoplasm and has e...
How far ‘AUG-proximity effect’ goes?
Pereira, Francisco J.C.; Teixeira, Alexandre; Kong, Jian; Silva, Ana Luísa; Liebhaber, Stephen A.; Romão, LuísaNonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and selectively degrades mRNAs carrying premature termination codons (PTCs). We have previously shown that mRNAs carrying a PTC located in close proximity to the translation initiation AUG codon escape NMD. This was called the “AUG-proximity effect”. The present work illustrates that the extension of the AUG-proximity effect, i.e. to w...
An upstream open reading frame regulates de translational efficiency of the hum...
Barbosa, Cristina; Romão, LuísaAmong the various cis-acting elements present in the 5’ leader sequence of mRNAs there are upstream open reading frames (uORFs). Although their function is still poorly understood, they are known to downregulate the main ORF expression of several human transcripts that code for key regulatory genes. The human erythropoietin (EPO) is a glycoprotein that was initially characterized has a hormone mainly synthesiz...
Translational control of the human hemojuvelin via upstream open reading frames
Onofre, Claudia; Barbosa, Cristina; Romão, LuísaIron is an essential element for many biological reactions carried out by living systems. A tight regulation of systemic iron homeostasis is crucial to avoid the pathological conditions of iron deficiency or overload. Juvenile hemochromatosis, is an early-onset inherited disorder associated to iron overload caused by mutations on the hepcidin gene or in the gene encoding hemojuvelin (HJV). HJV is a glycosylphos...
Alternative polyadenylation and nonsense-mediated decay coordinately regulate t...
Martins, Rute; Proença, Daniela; Silva, Bruno; Barbosa, Cristina; Silva, Ana Luísa; Faustino, Paula; Romão, LuísaNonsense-mediated decay (NMD) is an mRNA surveillance pathway that selectively recognizes and degrades defective mRNAs carrying premature translation-termination codons. However, several studies have shown that NMD also targets physiological transcripts that encode full-length proteins, modulating their expression. Indeed, some features of physiological mRNAs can render them NMD-sensitive. Human HFE is a MHC cl...
Unspliced Precursors of NMD-Sensitive β-Globin Transcripts Exhibit Decreased St...
Morgado, Ana; Almeida, Fátima; Silva, Ana Luísa; Romão, LuísaNonsense-mediated mRNA decay (NMD) is a quality control mechanism that detects and rapidly degrades mRNAs carrying premature translation-termination codons (PTCs). Mammalian NMD depends on both splicing and translation, and requires recognition of the premature stop codon by the cytoplasmic ribosomes. Surprisingly, some published data have suggested that nonsense codons may also affect the nuclear metabolism of...
Control of human beta-globin mRNA stability and its impact on beta-thalassemia ...
Peixeiro, Isabel; Silva, Ana Luísa; Romão, LuísaMessenger RNA (mRNA) stability is a critical determinant that affects gene expression. Many pathways have evolved to modulate mRNA stability in response to developmental, physiological and/or environmental stimuli. Eukaryotic mRNAs have a considerable range of half-lives, from as short as a few minutes to as long as several days. Human globin mRNAs constitute an example of highly stable mRNAs. However, a wide v...
Interaction of PABPC1 with the translation initiation complex is critical to th...
Peixeiro, Isabel; Inácio, Ângela; Barbosa, Cristina; Silva, Ana Luísa; Liebhaber, Stephen; Romão, LuísaNonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and rapidly degrades mRNAs containing premature termination codons (PTC). The strength of the NMD response appears to reflect multiple determinants on a target mRNA. We have previously reported that mRNAs containing PTCs in close proximity to the translation initiation codon (AUG-proximal PTCs) can substantially evade NMD. Here, we exp...
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