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.
- 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, Reviewing Editor, Johns Hopkins School of Medicine, United States
- Received: October 27, 2017
- Accepted: March 9, 2018
- Accepted Manuscript published: March 12, 2018 (version 1)
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