Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

RNA - Tập 17 Số 5 - Trang 843-854 - 2011
Gabriele Neu‐Yilik1, Beate Amthor2,3, Niels H. Gehring2,3, Sharif Bahri2, Helena Païdassi2, Matthias W. Hentze4,3, Andreas E. Kulozik2,3
1Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
2Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, 69120 Heidelberg, Germany
3Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany
4European Molecular Biology Laboratory, 69117 Heidelberg, Germany

Tóm tắt

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.

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RNA

Tập 17 Số 5

843-854

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