Defective microhomology-mediated end joining in SMARCB1-deficient tumors.

Rhabdoid tumors (RTs) are highly aggressive cancers driven by biallelic mutation of SMARCB1, a core subunit of the BAF (SWI/SNF) complex. We found that SMARCB1-deficient tumors have a defect in the microhomology-mediated end joining (MMEJ) pathway, and SMARCB1 is essential for maintaining the protein level of the core MMEJ protein, DNA Polymerase theta (PolΘ). Mechanistically, SMARCB1 facilitates the nuclear export of the POLQ mRNA through its interaction with the nuclear pore complex. Interestingly, loss of MMEJ in RT cells leads to a compensatory activation of, and a hyper-dependence on, the Fanconi Anemia (FA)/BRCA pathway. Notably, degraders of RBM39, a splicing modulator, show strong antitumor efficacy in RT models in vitro and in vivo by disrupting FA/BRCA pathway. SMARCB1 and other cBAF/pBAF components are important for maintenance of MMEJ activity and PolΘ protein level, suggesting that BAF-deficient cancers more broadly may be treated by targeted inhibition of the FA/BRCA pathway.