Spliceosomal disruption of the non-canonical BAF complex in cancer Journal Article
| Authors: | Inoue, D.; Chew, G. L.; Liu, B.; Michel, B. C.; Pangallo, J.; D’Avino, A. R.; Hitchman, T.; North, K.; Lee, S. C. W.; Bitner, L.; Block, A.; Moore, A. R.; Yoshimi, A.; Escobar-Hoyos, L.; Cho, H.; Penson, A.; Lu, S. X.; Taylor, J.; Chen, Y.; Kadoch, C.; Abdel-Wahab, O.; Bradley, R. K. |
| Article Title: | Spliceosomal disruption of the non-canonical BAF complex in cancer |
| Abstract: | SF3B1 is the most commonly mutated RNA splicing factor in cancer1–4, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L5–7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies. © 2019, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | gene mutation; exon; nonhuman; letter; gene; gene expression; genetic variability; wild type; xenograft; tumor growth; spliceosome; mutagenesis; mutant; dna degradation; antisense oligonucleotide; human; priority journal; bromodomain inhibitor; sf3b1 gene; rna splicing factor; malignant neoplasm; brd9 gene |
| Journal Title: | Nature |
| Volume: | 574 |
| Issue: | 7778 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2019-10-17 |
| Start Page: | 432 |
| End Page: | 436 |
| Language: | English |
| DOI: | 10.1038/s41586-019-1646-9 |
| PUBMED: | 31597964 |
| PROVIDER: | scopus |
| PMCID: | PMC6858563 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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