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

Edward J. Sanderlin, Melissa M. Keenan, Martin Mense, Alexey S. Revenko, Brett P. Monia, Shuling Guo and Lulu Huang ()
Additional contact information
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.

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-29935-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29935-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-29935-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().