Spliceosomal disruption of the non-canonical BAF complex in cancer.

ABSTRACT: SF3B1 is the most commonly mutated RNA splicing factor in cancer^1-4, 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 GLTSCR1L^5-7. 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 o

SUBMITTER: Inoue D 

PROVIDER: S-EPMC6858563 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature