Spliceosomal disruption of the non-canonical BAF complex in cancer.
| Publication Type | Academic Article |
| Authors | Inoue D, Chew G, Liu B, Michel B, Pangallo J, D'Avino A, Hitchman T, North K, Lee S, Bitner L, Block A, Moore A, Yoshimi A, Escobar-Hoyos L, Cho H, Penson A, Lu S, Taylor J, Chen Y, Kadoch C, Abdel-Wahab O, Bradley R |
| Journal | Nature |
| Volume | 574 |
| Issue | 7778 |
| Pagination | 432-436 |
| Date Published | 10/09/2019 |
| ISSN | 1476-4687 |
| Keywords | Chromosomal Proteins, Non-Histone, Neoplasms, RNA Splicing, Spliceosomes |
| 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. |
| DOI | 10.1038/s41586-019-1646-9 |
| PubMed ID | 31597964 |
| PubMed Central ID | PMC6858563 |