title: Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay.
abstract: mRNA surveillance pathways selectively clear defective mRNAs from the cell. As such, these pathways serve as important modifiers of genetic disorders. Nonsense-mediated decay (NMD), the most intensively studied surveillance pathway, recognizes mRNAs with premature termination codons (PTCs). In mammalian systems the location of a PTC more than 50 nucleotides 5' to the terminal exon-exon junction is a critical determinant of NMD. However, mRNAs with nonsense codons that fulfill this requirement but are located very early in the open reading frame can effectively evade NMD. The unexpected resistance of such mRNAs with AUG-proximal PTCs to accelerated decay suggests that important determinants of NMD remain to be identified. Here, we report that an NMD-sensitive mRNA can be stabilized by artificially tethering the cytoplasmic poly(A) binding protein 1, PABPC1, at a PTC-proximal position. Remarkably, the data further suggest that NMD of an mRNA with an AUG-proximal PTC can also be repressed by PABPC1, which might be brought into proximity with the PTC during cap-dependent translation and 43S scanning. These results reveal a novel parameter of NMD in mammalian cells that can account for the stability of mRNAs with AUG-proximal PTCs. These findings serve to expand current mechanistic models of NMD and mRNA translation.
authors.affiliation: Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Silva
authors.forename: Patrícia
authors.initials: P
authors.lastname: Ribeiro
authors.forename: Angela
authors.initials: A
authors.lastname: Inácio
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Liebhaber
authors.forename: Luísa
authors.initials: L
authors.lastname: Romão
mesh_terms: D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics*; D005914:Globins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D039122:Poly(A)-Binding Protein I / Q000378:metabolism*; D014176:Protein Biosynthesis; D020365:RNA Helicases; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; D039122:Poly(A)-Binding Protein I; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D015534:Trans-Activators; C026452:messenger ribonucleoprotein; D005914:Globins; D020365:RNA Helicases; C101828:UPF1 protein, human