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Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways

Pavel V Ivanov, Niels H Gehring, Joachim B Kunz, Matthias W Hentze, Andreas E Kulozik

Author Affiliations

  1. Pavel V Ivanov1,2,3,
  2. Niels H Gehring1,2,
  3. Joachim B Kunz1,2,
  4. Matthias W Hentze*,2,3 and
  5. Andreas E Kulozik*,1,2
  1. 1 Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
  2. 2 Molecular Medicine Partnership Unit, European Molecular Biology Laboratory and University of Heidelberg, Heidelberg, Germany
  3. 3 European Molecular Biology Laboratory, Heidelberg, Germany
  1. *Corresponding authors: Molecular Medicine Partnership Unit, European Molecular Biology Laboratory and University of Heidelberg, Heidelberg 69120, Germany. Tel.: +49 6221 387501; Fax: +49 6221 387518; E-mail: Matthias.Hentze{at}embl.de Department of Pediatric Oncology, Hematology and Immunology, Molecular Medicine Partnership Unit, University of Heidelberg, Im Neuenheimer Feld 156, Heidelberg 69120, Germany. Tel.: +49 6221 564555; Fax: +49 6221 564559; E-mail: andreas.kulozik{at}med.uni-heidelberg.de
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Abstract

Nonsense‐mediated mRNA decay (NMD) represents a key mechanism to control the expression of wild‐type and aberrant mRNAs. Phosphorylation of the protein UPF1 in the context of translation termination contributes to committing mRNAs to NMD. We report that translation termination is inhibited by UPF1 and stimulated by cytoplasmic poly(A)‐binding protein (PABPC1). UPF1 binds to eRF1 and to the GTPase domain of eRF3 both in its GTP‐ and GDP‐bound states. Importantly, mutation studies show that UPF1 can interact with the exon junction complex (EJC) alternatively through either UPF2 or UPF3b to become phosphorylated and to activate NMD. On this basis, we discuss an integrated model where UPF1 halts translation termination and is phosphorylated by SMG1 if the termination‐promoting interaction of PABPC1 with eRF3 cannot readily occur. The EJC, with UPF2 or UPF3b as a cofactor, interferes with physiological termination through UPF1. This model integrates previously competing models of NMD and suggests a mechanistic basis for alternative NMD pathways.

  • Received November 7, 2007.
  • Accepted January 18, 2008.
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