title: Interaction of PABPC1 with the translation initiation complex is critical to the NMD resistance of AUG-proximal nonsense mutations.
abstract: Nonsense-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 explore the mechanistic basis for this NMD resistance. We demonstrate that translation termination at an AUG-proximal PTC lacks the ribosome stalling that is evident in an NMD-sensitive PTC. This difference is associated with demonstrated interactions of the cytoplasmic poly(A)-binding protein 1, PABPC1, with the cap-binding complex subunit, eIF4G and the 40S recruitment factor eIF3 as well as the ribosome release factor, eRF3. These interactions, in combination, underlie critical 3'-5' linkage of translation initiation with efficient termination at the AUG-proximal PTC and contribute to an NMD-resistant PTC definition at an early phase of translation elongation.
authors: Departamento de Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors: Isabel
authors: I
authors: Peixeiro
authors: Ângela
authors: Â
authors: Inácio
authors: Cristina
authors: C
authors: Barbosa
authors: Ana Luísa
authors: AL
authors: Silva
authors: Stephen A
authors: SA
authors: Liebhaber
authors: Luísa
authors: L
authors: Romão
mesh_terms: D018387:Codon, Initiator; D018389:Codon, Nonsense; D018388:Codon, Terminator; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D010442:Peptide Chain Initiation, Translational; D010443:Peptide Chain Termination, Translational; D010454:Peptide Termination Factors / Q000378:metabolism; D039122:Poly(A)-Binding Protein I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry; D016601:RNA-Binding Proteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism
chemical_list: D018387:Codon, Initiator; D018389:Codon, Nonsense; D018388:Codon, Terminator; D039621:Eukaryotic Initiation Factor-3; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D010454:Peptide Termination Factors; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C087971:peptide-chain-release factor 3