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

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• dc.contributor.author Serrat Farran, Xènia, 1993-
• dc.contributor.author Kukhtar, Dmytro
• dc.contributor.author Cornes Maragliano, Eric, 1987-
• dc.contributor.author Esteve-Codina, Anna
• dc.contributor.author Benlloch, Helena
• dc.contributor.author Cecere, Germano
• dc.contributor.author Cerón Madrigal, Julián
• dc.date.accessioned 2020-04-07T08:47:53Z
• dc.date.available 2020-04-07T08:47:53Z
• dc.date.issued 2019
• dc.description.abstract 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Serrat X, Kukhtar D, Cornes E, Esteve-Codina A, Benlloch H, Cecere G, Cerón J. 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. PLoS Genet. 2019; 15(10):e1008464. DOI: 10.1371/journal.pgen.1008464
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1008464
• dc.identifier.issn 1553-7390
• dc.identifier.uri http://hdl.handle.net/10230/44177
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLoS Genet. 2019; 15(10):e1008464
• dc.rights © 2019 Serrat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Caenorhabditis elegans
• dc.subject.keyword RNA interference
• dc.subject.keyword Missense mutation
• dc.subject.keyword Larvae
• dc.subject.keyword Sequence motif analysis
• dc.subject.keyword Alleles
• dc.subject.keyword Mutant strains
• dc.subject.keyword CRISPR
• dc.title 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
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion