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Targeted pseudouridylation: An approach for suppressing nonsense mutations in disease genes.

Authors :
Adachi H
Pan Y
He X
Chen JL
Klein B
Platenburg G
Morais P
Boutz P
Yu YT
Source :
Molecular cell [Mol Cell] 2023 Feb 16; Vol. 83 (4), pp. 637-651.e9. Date of Electronic Publication: 2023 Feb 09.
Publication Year :
2023

Abstract

Nonsense mutations create premature termination codons (PTCs), activating the nonsense-mediated mRNA decay (NMD) pathway to degrade most PTC-containing mRNAs. The undegraded mRNA is translated, but translation terminates at the PTC, leading to no production of the full-length protein. This work presents targeted PTC pseudouridylation, an approach for nonsense suppression in human cells. Specifically, an artificial box H/ACA guide RNA designed to target the mRNA PTC can suppress both NMD and premature translation termination in various sequence contexts. Targeted pseudouridylation exhibits a level of suppression comparable with that of aminoglycoside antibiotic treatments. When targeted pseudouridylation is combined with antibiotic treatment, a much higher level of suppression is observed. Transfection of a disease model cell line (carrying a chromosomal PTC) with a designer guide RNA gene targeting the PTC also leads to nonsense suppression. Thus, targeted pseudouridylation is an RNA-directed gene-specific approach that suppresses NMD and concurrently promotes PTC readthrough.<br />Competing Interests: Declaration of interests A patent relating to this work was filed and granted. Y.-T.Y. serves as a member of the Scientific Advisory Board at ProQR Therapeutics.<br /> (Copyright © 2023 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1097-4164
Volume :
83
Issue :
4
Database :
MEDLINE
Journal :
Molecular cell
Publication Type :
Academic Journal
Accession number :
36764303
Full Text :
https://doi.org/10.1016/j.molcel.2023.01.009