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

• Verfasst von: Neu-Yilik, Gabriele [VerfasserIn]
• Verfasst von: Amthor, Beate [VerfasserIn]
• Verfasst von: Gehring, Niels H. [VerfasserIn]
• Verfasst von: Bahri, Sharif [VerfasserIn]
• Verfasst von: Paidassi, Helena [VerfasserIn]
• Verfasst von: Hentze, Matthias W. [VerfasserIn]
• Verfasst von: Kulozik, Andreas [VerfasserIn]
• Titel: Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon
• Verf.angabe: Gabriele Neu-Yilik, Beate Amthor, Niels H. Gehring, Sharif Bahri, Helena Paidassi, Matthias W. Hentze, and Andreas E. Kulozik
• Jahr: 2011
• Umfang: 12 S.
• Fussnoten: Gesehen am 22.09.2022
• Titel Quelle: Enthalten in: RNA
• Ort Quelle: Cold Spring Harbor, NY : Laboratory Press, 1995
• Jahr Quelle: 2011
• Band/Heft Quelle: 17(2011), 5, Seite 843-854
• ISSN Quelle: 1469-9001
• DOI: doi:10.1261/rna.2401811
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: NMD-resistant transcripts
• Sach-SW: nonsense-mediated mRNA decay
• Sach-SW: premature termination
• Sach-SW: translation reinitiation
• Sach-SW: β-thalassemia
• K10plus-PPN: 1817266217

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.