How mRNA translation can modulate nonsense-mediated decay

• Autor(a) principal: Romão, Luísa
• Data de Publicação: 2017
• Tipo de documento: Artigo de conferência
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.18/5423
• topic: Gene Mutations; Nonsense-mediated Decay (NMD); Expressão Génica; Genómica Funcional e Estrutural

About one third of the gene mutations found in human genetic disorders, including cancer, result in premature translation-termination codons (PTCs) and the rapid degradation of the corresponding mRNAs by nonsense-mediated decay (NMD). However, we have found that human mRNAs with a PTC in close proximity to the translation initiation codon (AUG-proximal PTC) can substantially escape NMD, which contradicts the current models for this mechanism. In fact, our data support a model in which cytoplasmic poly(A)-binding protein 1 (PABPC1) is brought into close proximity with an AUG-proximal PTC via interactions with the translation initiation complexes. This proximity of PABPC1 to the AUG-proximal PTC allows PABPC1 to interact with eukaryotic release factor 3 (eRF3) with a consequent enhancement of the termination reaction and repression of the NMD response. Here, I will provide strong evidence that the eukaryotic initiation factor 3 (eIF3) is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC, and I will dissect the biochemical interactions of the eIF3 subunits in bridging PABPC1/eIF4G complex to the 40S ribosomal subunit.