title: Resistance of mRNAs with AUG-proximal nonsense mutations to nonsense-mediated decay reflects variables of mRNA structure and translational activity.
abstract: Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and selectively degrades mRNAs carrying premature termination codons (PTCs). The level of sensitivity of a PTC-containing mRNA to NMD is multifactorial. We have previously shown that human β-globin mRNAs carrying PTCs in close proximity to the translation initiation AUG codon escape NMD. This was called the 'AUG-proximity effect'. The present analysis of nonsense codons in the human α-globin mRNA illustrates that the determinants of the AUG-proximity effect are in fact quite complex, reflecting the ability of the ribosome to re-initiate translation 3' to the PTC and the specific sequence and secondary structure of the translated ORF. These data support a model in which the time taken to translate the short ORF, impacted by distance, sequence, and structure, not only modulates translation re-initiation, but also impacts on the exact boundary of AUG-proximity protection from NMD.
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors.forename: Francisco J C
authors.initials: FJ
authors.lastname: Pereira
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal Centro de Investigação em Genética Molecular Humana, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1349-008 Lisboa, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: Departments of Genetics and Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Kong
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal BioISI - Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barbosa
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Silva
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Marques-Ramos
authors.affiliation: Departments of Genetics and Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Liebhaber
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal BioISI - Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal luisa.romao@insa.min-saude.pt.
authors.forename: Luísa
authors.initials: L
authors.lastname: Romão
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018387:Codon, Initiator; D018389:Codon, Nonsense; D006801:Humans; D051379:Mice; D059365:Nonsense Mediated mRNA Decay; D016366:Open Reading Frames; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000737:chemistry*; D055542:alpha-Globins / Q000235:genetics; D055544:beta-Globins / Q000235:genetics
chemical_list: D018387:Codon, Initiator; D018389:Codon, Nonsense; D012333:RNA, Messenger; D055542:alpha-Globins; D055544:beta-Globins