CRISPR editing of sftb-1/SF3B1 in C. elegans allows the identification of synthetic interactions with cancer-related mutations and the chemical inhibition of splicing
Serrat, X.; Kukhtar, D.; Cornes, E.; Esteve-Codina, A.; Benlloch, H.; Cecere, G.; Ceron, J.
Show abstract
SF3B1 is the most frequently mutated splicing factor in cancer. Mutations in SF3B1 confer growth advantages to cancer cells but they may also confer vulnerabilities that can be therapeutically targeted. In contrast to other animal models, 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 inhibitor pladienolide B. Thus, we have established a multicellular model for SF3B1 mutations amenable for high-throughput genetic and chemical screens.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Critical contribution of 3' non-seed base pairing to the in vivo function of the evolutionarily conserved let-7a microRNA 96%
- Simultaneous suppression of ribosome biogenesis and Tor activation by TRIM-NHL proteins promotes terminal differentiation 95%
- Defining the roles of the Integrator, NEXT, and nuclear exosome complexes in Drosophila oogenesis 95%
Similar papers in this journal
Similar papers in this journal
- A neural m6A/YTHDF pathway is required for learning and memory in Drosophila 95%
- Arginine methylation promotes siRNA-binding specificity for a spermatogenesis-specific isoform of the Argonaute protein CSR-1 95%
- GLH/VASA helicases promote germ granule formation to ensure the fidelity of piRNA-mediated transcriptome surveillance 94%
Similar papers in this journal
- Catalytic activity of the Bin3/MEPCE methyltransferase domain is dispensable for 7SK snRNP function in Drosophila melanogaster 96%
- Germline maintenance through the multifaceted activities of GLH/Vasa in Caenorhabditis elegans P granules 95%
- A stress-dependent postembryonic role for the core CPA factor CFIM-1 in germline integrity 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.