Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression
Amy E. Campbell,
Michael C. Dyle,
Roberto Albanese,
Tyler Matheny,
Kavitha Sudheendran,
Michael A. Cortázar,
Thomas Forman,
Rui Fu,
Austin E. Gillen,
Marvin H. Caruthers,
Stephen N. Floor,
Lorenzo Calviello,
Sujatha Jagannathan
Affiliations
Amy E. Campbell
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Michael C. Dyle
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Roberto Albanese
Functional Genomics Research Centre, Human Technopole, 20157 Milan, Italy; Computational Biology Research Centre, Human Technopole, 20157 Milan, Italy
Tyler Matheny
RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kavitha Sudheendran
Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA
Michael A. Cortázar
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Thomas Forman
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
Rui Fu
RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Austin E. Gillen
RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Marvin H. Caruthers
Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA
Stephen N. Floor
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
Lorenzo Calviello
Functional Genomics Research Centre, Human Technopole, 20157 Milan, Italy; Computational Biology Research Centre, Human Technopole, 20157 Milan, Italy
Sujatha Jagannathan
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; Corresponding author
Summary: 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.
