Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1

Cell Rep. 2018 May 15;23(7):2186-2198. doi: 10.1016/j.celrep.2018.04.039.

Abstract

The splicing factor SRSF1 promotes nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs with premature termination codons (PTCs). Here we show that transcript-bound SRSF1 increases the binding of NMD factor UPF1 to mRNAs while in, or associated with, the nucleus, bypassing UPF2 recruitment and promoting NMD. SRSF1 promotes NMD when positioned downstream of a PTC, which resembles the mode of action of exon junction complex (EJC) and NMD factors. Moreover, splicing and/or EJC deposition increase the effect of SRSF1 on NMD. Lastly, SRSF1 enhances NMD of PTC-containing endogenous transcripts that result from various events. Our findings reveal an alternative mechanism for UPF1 recruitment, uncovering an additional connection between splicing and NMD. SRSF1's role in the mRNA's journey from splicing to decay has broad implications for gene expression regulation and genetic diseases.

Keywords: EJC; NMD; RNA splicing; SRSF1; UPF1.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics
  • Amino Acid Motifs
  • Cell Nucleus / metabolism
  • Codon, Nonsense / genetics
  • Exons / genetics
  • HeLa Cells
  • Humans
  • Models, Genetic
  • Nonsense Mediated mRNA Decay / genetics*
  • Phosphorylation
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors / chemistry
  • Serine-Arginine Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / metabolism*
  • Transcription Factors / metabolism

Substances

  • Codon, Nonsense
  • RNA, Messenger
  • RNA-Binding Proteins
  • SRSF1 protein, human
  • Transcription Factors
  • UPF2 protein, human
  • UPF3B protein, human
  • Serine-Arginine Splicing Factors