Interaction of PABPC1 with the translation initiation complex is critical to the NMD resistance of AUG-proximal nonsense mutations

Nucleic Acids Res. 2012 Feb;40(3):1160-73. doi: 10.1093/nar/gkr820. Epub 2011 Oct 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Codon, Initiator
  • Codon, Nonsense*
  • Codon, Terminator
  • Eukaryotic Initiation Factor-3 / metabolism
  • Eukaryotic Initiation Factor-4G / metabolism
  • Eukaryotic Initiation Factors / metabolism*
  • HeLa Cells
  • Humans
  • Nonsense Mediated mRNA Decay*
  • Peptide Chain Initiation, Translational
  • Peptide Chain Termination, Translational
  • Peptide Termination Factors / metabolism
  • Poly(A)-Binding Protein I / antagonists & inhibitors
  • Poly(A)-Binding Protein I / metabolism*
  • RNA, Messenger / chemistry
  • RNA-Binding Proteins / metabolism
  • Ribosomes / metabolism

Substances

  • Codon, Initiator
  • Codon, Nonsense
  • Codon, Terminator
  • Eukaryotic Initiation Factor-3
  • Eukaryotic Initiation Factor-4G
  • Eukaryotic Initiation Factors
  • Peptide Termination Factors
  • Poly(A)-Binding Protein I
  • RNA, Messenger
  • RNA-Binding Proteins
  • peptide-chain-release factor 3