Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon
- Gabriele Neu-Yilik1,2,
- Beate Amthor1,2,
- Niels H. Gehring1,2,4,
- Sharif Bahri1,5,
- Helena Paidassi1,6,
- Matthias W. Hentze2,3 and
- Andreas E. Kulozik1,2
- 1Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany
- 2Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany
- 3European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Abstract
The degradation of nonsense-mutated β-globin mRNA by nonsense-mediated mRNA decay (NMD) limits the synthesis of C-terminally truncated dominant negative β-globin chains and thus protects the majority of heterozygotes from symptomatic β-thalassemia. β-globin mRNAs with nonsense mutations in the first exon are known to bypass NMD, although current mechanistic models predict that such mutations should activate NMD. A systematic analysis of this enigma reveals that (1) β-globin exon 1 is bisected by a sharp border that separates NMD-activating from NMD-bypassing nonsense mutations and (2) the ability to bypass NMD depends on the ability to reinitiate translation at a downstream start codon. The data presented here thus reconcile the current mechanistic understanding of NMD with the observed failure of a class of nonsense mutations to activate this important mRNA quality-control pathway. Furthermore, our data uncover a reason why the position of a nonsense mutation alone does not suffice to predict the fate of the affected mRNA and its effect on protein expression.
Keywords
- nonsense-mediated mRNA decay
- NMD-resistant transcripts
- premature termination
- β-thalassemia
- translation reinitiation
Footnotes
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Reprint requests to: Andreas E. Kulozik, Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, 69120 Heidelberg, Germany; e-mail: Andreas.Kulozik{at}med.uni-heidelberg.de; or Matthias W. Hentze, Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany; e-mail: hentze{at}embl.de; fax: 49 6221 564580.
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Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.2401811.
- Received August 2, 2010.
- Accepted January 31, 2011.
- Copyright © 2011 RNA Society
Freely available online through the RNA Open Access option.