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SF3B1-K700E Drives Oncogenic Alternative Splicing of Cell Cycle Checkpoint Genes in Cancer

ABSTRACT: Pre-mRNA splicing plays a crucial role in maintaining cellular homeostasis, with strict regulation required for processes such as cell cycle progression. SF3B1, a core component of the spliceosome, has emerged as a key player in alternative splicing regulation and is frequently mutated in cancer. Among these mutations, SF3B1K700E disrupts normal splicing patterns and deregulates cell cycle control. In this study, we investigate the impact of SF3B1 phosphorylation on cell cycle-dependent splicing, with a particular focus on the checkpoint regulators ARPP19 and ENSA, two functionally related proteins that modulate PP2A-B55 activity during mitotic progression. Using RNA-seq analysis, we identify a subset of SF3B1-regulated splicing events that are enriched in cell cycle genes. We demonstrate that SF3B1 phosphorylation during G2/M promotes ARPP19-long isoform inclusion, a variant associated with poor survival in AML patients and accelerated mitotic exit. Notably, we show that inhibition of SF3B1 reverses the splicing changes induced by SF3B1K700E, reducing the levels of ARPP19-long and suggesting a potential therapeutic strategy for cancers with spliceosome mutations. Our findings highlight a direct link between SF3B1-dependent splicing, cell cycle progression, and tumorigenesis, providing new insights into the molecular mechanisms underlying cancer-associated splicing dysregulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310035 | GEO | 2026/02/25

REPOSITORIES: GEO

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SF3B1 K700E Mutation Induces Genome-Wide Enhancement of Transcriptional Pause Release in ES Cells [PRO-seq]

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Physiologic expression of Sf3b1K700E causes impaired erythropoieses, aberrant splicing, and sensitivity to pharmacologic spliceosome modulation

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Project description:Splicing Factor 3b Subunit 1 (SF3B1), a core component of the spliceosome, undergoes dynamic phosphorylation and dephosphorylation during the splicing cycle to regulate pre-mRNA splicing. Twenty-eight threonine/proline repeats are phosphorylated by CDK11 during spliceosome activation and remain phosphorylated in the catalytically active spliceosomes. The function of phosphorylated SF3B1 (P-SF3B1), and the identity of spliceosomes stalled by CDK11 inhibition remain unclear. Using quantitative proteomics of chromatin-associated spliceosomes, we identify a previously uncharacterized intermediate complex BOTS964, arrested by CDK11 inhibitor OTS964, that incorporates the nineteen-related (NTR) but not nineteen (NTC) complex. iCLIP-seq revealed that P-SF3B1 engages with the U6 snRNA internal stem-loop (ISL), suggesting a potential role in stabilizing the RNA catalytic core. We further demonstrate that P-SF3B1 is recognized by forkhead-associated (FHA) domain of SNIP1, which promotes recruitment of retention and splicing (RES) complex during spliceosome activation. Acute SNIP1 depletion disrupts RES incorporation, causes widespread splicing defects, and promotes hyperphosphorylation of SF3B1 by CDK11. Mutations in SNIP1 FHA domain, including the neurodevelopmental disorder associated E366G variant, impair P-SF3B1 binding, pre-mRNA splicing, and cell viability. Together, these findings uncover the phosphorylation-dependent CDK11/P-SF3B1/SNIP1 signaling axis that is critical for pre-mRNA splicing and cellular proliferation and provide a mechanistic insight into its dysregulation in disease.

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