Spliceosomal disruption of the non-canonical BAF complex in cancer
| Autor: | Sydney X. Lu, Yu Chen, Daichi Inoue, Justin Taylor, Ariele Block, Robert K. Bradley, Cigall Kadoch, Alex Penson, Andrew R. D’Avino, Khrystyna North, Bo Liu, Brittany C. Michel, Hana Cho, Tyler D. Hitchman, Guo-Liang Chew, Stanley Chun-Wei Lee, Akihide Yoshimi, Joseph Pangallo, Luisa F. Escobar-Hoyos, Omar Abdel-Wahab, Lillian Bitner, Amanda R. Moore |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chromosomal Proteins Non-Histone RNA Splicing Mutant Mutagenesis (molecular biology technique) Biology medicine.disease_cause Article law.invention 03 medical and health sciences Exon Mice 0302 clinical medicine law Cell Line Tumor Neoplasms medicine Animals Humans Psychological repression Multidisciplinary Alternative splicing Chromatin Assembly and Disassembly Phosphoproteins 3. Good health Cell biology 030104 developmental biology 030220 oncology & carcinogenesis RNA splicing Spliceosomes Suppressor RNA Splicing Factors Carcinogenesis Neoplasm Transplantation Transcription Factors |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. A range of SF3B1 mutations promote tumorigenesis through the repression of BRD9, a core component of the non-canonical BAF complex, and correcting BRD9 mis-splicing in these SF3B1-mutant cells suppresses tumour growth. |
| Databáze: | OpenAIRE |
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