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.
Highlights
Deregulated RNA splicing is emerging as a new hallmark of cancer following the discovery of several splicing factor genes harboring somatic mutations in different tumor types [1]
SF3B1 encodes a splicing factor frequently mutated in hematological malignancies, and with less frequency in other solid tumors
Each SF3B1 mutation is predominant in a cancer type, indicating cell type-specific pathogenic mechanisms
Summary
Deregulated RNA splicing is emerging as a new hallmark of cancer following the discovery of several splicing factor genes harboring somatic mutations in different tumor types [1]. SF3B1, a core component of the U2 snRNP, is the most frequently mutated splicing factor in human cancers. RNA-sequencing (RNA-seq) analyses in different tumor types and cell lines with SF3B1 missense mutations, including the most prevalent substitution K700E, identified distinct alternative splicing (AS) defects [13,14,15]. Taking advantage of the extraordinary conservation of splicing factors across evolution and the ease of genetic manipulation of C. elegans, we established a multicellular model to study SF3B1 cancer-related mutations. Spliceosome components, and SF3B1, are being intensively studied as targets of antitumor drugs [20,21,22]. We edited four amino acids to humanize the HEAT repeat 15 in SFTB-1, making C. elegans sensitive to splicing modulators. We have created the first C. elegans strain sensitive to PB and HB, which would facilitate the chemical modulation of splicing in this model system
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