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.
ICE1 promotes the link between splicing and nonsense- mediated mRNA decayPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE105436).
- Thomas D Baird
- J Robert Hogg
- Ken Chih-Chien Cheng
- Yu-Chi Chen
- Eugen Buehler
- Scott E Martin
- James Inglese
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Rachel Green, Johns Hopkins School of Medicine, United States
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