Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon
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...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2011
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| In: |
RNA
Year: 2011, Volume: 17, Issue: 5, Pages: 843-854 |
| ISSN: | 1469-9001 |
| DOI: | 10.1261/rna.2401811 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1261/rna.2401811 Verlag, lizenzpflichtig, Volltext: http://rnajournal.cshlp.org/content/17/5/843 
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| Author Notes: | Gabriele Neu-Yilik, Beate Amthor, Niels H. Gehring, Sharif Bahri, Helena Paidassi, Matthias W. Hentze, and Andreas E. Kulozik |
| Summary: | 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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| Item Description: | Gesehen am 22.09.2022 |
| Physical Description: | Online Resource |
| ISSN: | 1469-9001 |
| DOI: | 10.1261/rna.2401811 |