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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
Author: Serrat, Xènia
Kukhtar, Dmytro
Cornes, Eric
Esteve Codina, Anna
Benlloch, Helena
Cecere, Germano
Cerón Madrigal, Julián
Keywords: Mutació (Biologia)
Mutation (Biology)
Issue Date: 1-Oct-2019
Publisher: Public Library Science
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 or herboxidiene. Thus, we have established a multicellular model for SF3B1 mutations amenable for high-throughput genetic and chemical screens.
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It is part of: Plos Genetics, 2019-10-01, Vol. 15, Issue 10
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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