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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Spliceosomal disruption of the non-canonical BAF complex in cancer

Daichi Inoue1,2, Guo-Liang Chew3,4, Bo Liu1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature
|October 11, 2019
PubMed

Insights

Mutations in SF3B1 splicing factor cause cancer by repressing BRD9. Correcting BRD9 splicing in SF3B1-mutant cells suppresses tumor growth, suggesting new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • SF3B1 mutations are common in cancer, but their oncogenic mechanisms remain unclear.
  • RNA splicing factors play critical roles in gene expression and are frequently altered in malignancies.

Purpose of the Study:

  • To identify splicing alterations driving tumorigenesis.
  • To elucidate the functional consequences of SF3B1 mutations in cancer.

Main Methods:

  • Integrated pan-cancer splicing analyses.
  • Positive-enrichment CRISPR screening to identify cancer-promoting splicing events.
  • Antisense oligonucleotide and CRISPR-directed mutagenesis for therapeutic correction.

Main Results:

  • Diverse SF3B1 mutations converge on the repression of BRD9, a component of the non-canonical BAF complex.
  • Mutant SF3B1 induces BRD9 mRNA degradation via aberrant splicing, leading to loss of non-canonical BAF.
  • BRD9 functions as a tumor suppressor, particularly in uveal melanoma.
  • Restoring BRD9 splicing suppresses tumor growth in SF3B1-mutant cells.

Conclusions:

  • Disruption of the non-canonical BAF complex by SF3B1 mutations contributes to diverse cancers.
  • Targeting BRD9 splicing represents a potential mechanism-based therapeutic strategy for SF3B1-mutant malignancies.

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