title: Harnessing short poly(A)-binding protein-interacting peptides for the suppression of nonsense-mediated mRNA decay.
abstract: Nonsense-mediated mRNA decay (NMD) is a cellular process that eliminates messenger RNA (mRNA) substrates with premature translation termination codons (PTCs). In addition, NMD regulates the expression of a number of physiological mRNAs, for example transcripts containing long 3' UTRs. Current models implicate the interaction between cytoplasmic poly(A)-binding protein (PABPC1) and translation termination in NMD. Accordingly, PABPC1 present within close proximity of a termination codon antagonizes NMD. Here, we use reporter mRNAs with different NMD-inducing 3' UTRs to establish a general NMD-inhibiting property of PABPC1. NMD-inhibition is not limited to PABPC1, but can also be achieved by peptides consisting of the PABP-interacting motif 2 (PAM2) of different proteins when recruited to an NMD-inhibiting position of NMD reporter transcripts. The short PAM2 peptides efficiently suppress NMD activated by a long 3' UTR, an exon-junction complex (EJC) and individual EJC components, and stabilize a PTC-containing β-globin mRNA. In conclusion, our results establish short PABPC1-recruiting peptides as potent but position-dependent inhibitors of mammalian NMD.
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fatscher
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Niels H
authors.initials: NH
authors.lastname: Gehring
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D018389:Codon, Nonsense; D010454:Peptide Termination Factors; D010455:Peptides; D039122:Poly(A)-Binding Protein I; D039102:Poly(A)-Binding Proteins; D012333:RNA, Messenger; D055544:beta-Globins; C087971:peptide-chain-release factor 3