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Internal ribosome entry sequence‐mediated translation initiation triggers nonsense‐mediated decay

Jill A Holbrook, Gabriele Neu‐Yilik, Niels H Gehring, Andreas E Kulozik, Matthias W Hentze

Author Affiliations

  1. Jill A Holbrook1,2,
  2. Gabriele Neu‐Yilik1,2,
  3. Niels H Gehring1,2,
  4. Andreas E Kulozik*,1,2 and
  5. Matthias W Hentze*,1,3
  1. 1 Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, University Hospital Heidelberg, Im Neuenheimer Feld 150, Heidelberg, 69120, Germany
  2. 2 Department for Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 150, Heidelberg, 69120, Germany
  3. 3 Gene Expression Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 69117, Germany
  1. *Tel: +49 6221 56 2303; Fax: +49 6221 56 4559; E‐mail: andreas.kulozik{at}med.uni-heidelberg.de or Tel: +49 6221 387 501; Fax: +49 6221 387 518; E‐mail: hentze{at}embl.de
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Abstract

In eukaryotes, a surveillance pathway known as nonsense‐mediated decay (NMD) regulates the abundance of messenger RNAs containing premature termination codons (PTCs). In mammalian cells, it has been asserted that the NMD‐relevant first round of translation is special and involves initiation by a specific protein heterodimer, the nuclear cap‐binding complex (CBC). Arguing against a requirement for CBC‐mediated translation initiation, we show that ribosomal recruitment by the internal ribosomal entry sequence of the encephalomyocarditis virus triggers NMD of a PTC‐containing transcript under conditions in which ribosome entry from the cap is prohibited. These data generalize the previous model and suggest that translation per se, irrespective of how it is initiated, can mediate NMD.

  • Received March 2, 2006.
  • Revision received May 8, 2006.
  • Accepted May 10, 2006.
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