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SF3B1  is the most frequently mutated splicing factor in cancer. Mutations in  SF3B1  likely confer clonal advantages to cancer cells but they may also confer vulnerabilities that can be therapeutically targeted.  SF3B1  cancer mutations can be maintained in homozygosis in  C .  elegans , allowing synthetic lethal screens with a homogeneous population of animals. These mutations cause alternative splicing (AS) defects in  C .  elegans , as it occurs in  SF3B1 -mutated human cells. In a screen, we identified RNAi of U2 snRNP components that cause synthetic lethality with  sftb-1/SF3B1  mutations. We also detected synthetic interactions between  sftb-1  mutants and cancer-related mutations in  uaf-2/U2AF1  or  rsp-4/SRSF2 , demonstrating that this model can identify interactions between mutations that are mutually exclusive in human tumors. Finally, we have edited an SFTB-1 domain to sensitize  C .  elegans  to the splicing modulators pladienolide B and herboxidiene. Thus, we have established a multicellular model for  SF3B1  mutations amenable for high-throughput genetic and chemical screens.

plos genetics

CRISPR editing of sftb-1/SF3B1 in Caenorhabditis elegans allows the identification of synthetic interactions with cancer-related mutations and the chemical inhibition of splicing