Written by Austin Herbert
This week in journal club we discussed the paper “Nonsense-Mediated RNA Decay is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations” by Cheruiyot et al. Here, the authors conduct a crispr/cas9 knockout based forward genetic screen to identify previously unknown promoters of nonsense-mediated decay. Top hits from this screen included known NMD-associated factors UPF1, SMG6, and RUVBL1, and previously reported splicing factors not typically associated with NMD, SF3B1 and U2AF1. Both SF3B1 and U2AF1 contain reoccurring hotspot mutations involved in different types of cancers and thus were targeted for their unconventional roles in NMD. Cell lines created with these splicing factor hotspot mutations showed a distinct sensitivity to NMD inhibition, as cells exhibited various cancer related phenotypes such as reduced survivability, increased chromosomal aberrations and R-loop formations, and reduction in DNA replication and transcription fork progression speed. This paper sets the ground work for determining the specific interactions between splicing factors and the NMD pathway.