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CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway

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  • Edward J. Sanderlin

    (Ionis Pharmaceuticals, Inc.)

  • Melissa M. Keenan

    (Ionis Pharmaceuticals, Inc.)

  • Martin Mense

    (Cystic Fibrosis Foundation Therapeutics Lab, Cystic Fibrosis Foundation)

  • Alexey S. Revenko

    (Ionis Pharmaceuticals, Inc.)

  • Brett P. Monia

    (Ionis Pharmaceuticals, Inc.)

  • Shuling Guo

    (Ionis Pharmaceuticals, Inc.)

  • Lulu Huang

    (Ionis Pharmaceuticals, Inc.)

Abstract

Approximately 10% of cystic fibrosis patients harbor nonsense mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which can generate nonsense codons in the CFTR mRNA and subsequently activate the nonsense-mediated decay (NMD) pathway resulting in rapid mRNA degradation. However, it is not known which NMD branches govern the decay of CFTR mRNAs containing nonsense codons. Here we utilize antisense oligonucleotides targeting NMD factors to evaluate the regulation of nonsense codon-containing CFTR mRNAs by the NMD pathway. We observe that CFTR mRNAs with nonsense codons G542X, R1162X, and W1282X, but not Y122X, require UPF2 and UPF3 for NMD. Furthermore, we demonstrate that all evaluated CFTR mRNAs harboring nonsense codons are degraded by the SMG6-mediated endonucleolytic pathway rather than the SMG5-SMG7-mediated exonucleolytic pathway. Finally, we show that upregulation of all evaluated CFTR mRNAs with nonsense codons by NMD pathway inhibition improves outcomes of translational readthrough therapy.

Suggested Citation

  • Edward J. Sanderlin & Melissa M. Keenan & Martin Mense & Alexey S. Revenko & Brett P. Monia & Shuling Guo & Lulu Huang, 2022. "CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29935-9
    DOI: 10.1038/s41467-022-29935-9
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    1. Jyoti Sharma & Ming Du & Eric Wong & Venkateshwar Mutyam & Yao Li & Jianguo Chen & Jamie Wangen & Kari Thrasher & Lianwu Fu & Ning Peng & Liping Tang & Kaimao Liu & Bini Mathew & Robert J. Bostwick & , 2021. "A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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