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

Cell Rep. 2023 Jun 27;42(6):112642. doi: 10.1016/j.celrep.2023.112642. Epub 2023 Jun 13.


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.

Keywords: CP: Molecular biology; DUX4; FSHD; NMD; RNA decay; dystrophy; muscular; quality control; splicing; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation
  • Humans
  • Muscular Dystrophy, Facioscapulohumeral* / genetics
  • Muscular Dystrophy, Facioscapulohumeral* / metabolism
  • Nonsense Mediated mRNA Decay*
  • RNA / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors / metabolism


  • RNA
  • RNA-Binding Proteins
  • Serine-Arginine Splicing Factors
  • SRSF3 protein, human
  • DUX4L1 protein, human