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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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Hauptverfasser: Neu-Yilik, Gabriele (VerfasserIn) , Amthor, Beate (VerfasserIn) , Gehring, Niels H. (VerfasserIn) , Bahri, Sharif (VerfasserIn) , Paidassi, Helena (VerfasserIn) , Hentze, Matthias W. (VerfasserIn) , Kulozik, Andreas (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2011
In: RNA
Year: 2011, Jahrgang: 17, Heft: 5, Pages: 843-854
ISSN:1469-9001
DOI:10.1261/rna.2401811
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1261/rna.2401811
Verlag, lizenzpflichtig, Volltext: http://rnajournal.cshlp.org/content/17/5/843
Volltext
Verfasserangaben:Gabriele Neu-Yilik, Beate Amthor, Niels H. Gehring, Sharif Bahri, Helena Paidassi, Matthias W. Hentze, and Andreas E. Kulozik
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 22.09.2022
Beschreibung:Online Resource
ISSN:1469-9001
DOI:10.1261/rna.2401811

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