ICE1 promotes the link between splicing and nonsense-mediated mRNA decay

Elife. 2018 Mar 12;7:e33178. doi: 10.7554/eLife.33178.

Abstract

The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5-10% of non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens in model organisms; however, the increased complexity of gene expression regulation in human cells suggests that additional proteins may participate in the human NMD pathway. To identify proteins required for NMD, we performed a genome-wide RNAi screen against >21,000 genes. Canonical members of the NMD pathway were highly enriched as top hits in the siRNA screen, along with numerous candidate NMD factors, including the conserved ICE1/KIAA0947 protein. RNAseq studies reveal that depletion of ICE1 globally enhances accumulation and stability of NMD-target mRNAs. Further, our data suggest that ICE1 uses a putative MIF4G domain to interact with exon junction complex (EJC) proteins and promotes the association of the NMD protein UPF3B with the EJC.

Keywords: ICE1; RNA quality control; UPF3B; biochemistry; chemical biology; chromosomes; exon junction complex; genes; human; nonsense-mediated mRNA decay; siRNA screen.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Carrier Proteins / genetics*
  • Codon, Nonsense / genetics
  • Exons / genetics
  • Gene Expression Regulation
  • Humans
  • Nonsense Mediated mRNA Decay / genetics*
  • Protein Biosynthesis / genetics*
  • Protein Domains / genetics
  • RNA Interference
  • RNA Splicing / genetics*
  • RNA-Binding Proteins / genetics*
  • Ribosomal Proteins / genetics

Substances

  • Carrier Proteins
  • Codon, Nonsense
  • ICE1 protein, human
  • RNA-Binding Proteins
  • Ribosomal Proteins
  • UPF3B protein, human