Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression.

Autor:	Campbell AE; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Dyle MC; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Albanese R; Functional Genomics Research Centre, Human Technopole, 20157 Milan, Italy; Computational Biology Research Centre, Human Technopole, 20157 Milan, Italy., Matheny T; RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Sudheendran K; Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA., Cortázar MA; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Forman T; Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Fu R; RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Gillen AE; RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Caruthers MH; Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA., Floor SN; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., Calviello L; Functional Genomics Research Centre, Human Technopole, 20157 Milan, Italy; Computational Biology Research Centre, Human Technopole, 20157 Milan, Italy., Jagannathan S; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: sujatha.jagannathan@cuanschutz.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Jun 27; Vol. 42 (6), pp. 112642. Date of Electronic Publication: 2023 Jun 13.
DOI:	10.1016/j.celrep.2023.112642
Abstrakt:	Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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