Spliceosomal disruption of the non-canonical BAF complex in cancer

Daichi Inoue, Guo-Liang Chew, Bo Liu, Brittany C. Michel, Joseph Pangallo, Andrew R. D’Avino, Tyler Hitchman, Khrystyna North, Stanley Chun-Wei Lee, Lillian Bitner, Ariele Block, Amanda R. Moore, Akihide Yoshimi, Luisa Escobar-Hoyos, Hana Cho, Alex Penson, Sydney X. Lu, Justin Taylor, Yu Chen, Cigall Kadoch, Omar Abdel-Wahab () and Robert K. Bradley ()
Additional contact information
Daichi Inoue: Memorial Sloan Kettering Cancer Center
Guo-Liang Chew: Fred Hutchinson Cancer Research Center
Bo Liu: Memorial Sloan Kettering Cancer Center
Brittany C. Michel: Dana-Farber Cancer Institute
Joseph Pangallo: Fred Hutchinson Cancer Research Center
Andrew R. D’Avino: Broad Institute of MIT and Harvard
Tyler Hitchman: Memorial Sloan Kettering Cancer Center
Khrystyna North: Fred Hutchinson Cancer Research Center
Stanley Chun-Wei Lee: Memorial Sloan Kettering Cancer Center
Lillian Bitner: Memorial Sloan Kettering Cancer Center
Ariele Block: Memorial Sloan Kettering Cancer Center
Amanda R. Moore: Memorial Sloan Kettering Cancer Center
Akihide Yoshimi: Memorial Sloan Kettering Cancer Center
Luisa Escobar-Hoyos: Memorial Sloan Kettering Cancer Center
Hana Cho: Memorial Sloan Kettering Cancer Center
Alex Penson: Memorial Sloan Kettering Cancer Center
Sydney X. Lu: Memorial Sloan Kettering Cancer Center
Justin Taylor: Memorial Sloan Kettering Cancer Center
Yu Chen: Memorial Sloan Kettering Cancer Center
Cigall Kadoch: Broad Institute of MIT and Harvard
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center
Robert K. Bradley: Fred Hutchinson Cancer Research Center

Nature, 2019, vol. 574, issue 7778, 432-436

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1646-9

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