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bioRxiv · 10.1101/2025.11.20.689563

Defective Microhomology-Mediated End-joining in SMARCB1-Deficient Tumors

Zhu, G.·Asada, S.·Nguyen, H.·Hirohashi, Y.·Sun, L.·Mukkavalli, S.·Saravanapavan, A.·Shapiro, G. I.·D'Andrea, A. D.
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Abstract

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 Polymerase Q (POLQ). 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. Knockout or inhibition of this pathway selectively kills RT cells. Notably, RBM39 degraders, novel splicing modulators, effectively inhibit the FA/BRCA pathway and kill RT cells. SMARCB1 and other cBAF/pBAF components are important for maintenance of MMEJ activity and POLQ protein level, suggesting that BAF-deficient cancers more broadly may be treated by targeted inhibition of the FA/BRCA pathway. TeaserSMARCB1-deficient tumors lose POLQ protein and MMEJ repair, forcing a hyper-dependence on the FA/BRCA pathway.

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Zhu, G., Asada, S., Nguyen, H., Hirohashi, Y., Sun, L., Mukkavalli, S., Saravanapavan, A., Shapiro, G. I., D'Andrea, A. D.. 2025-11-21. Defective Microhomology-Mediated End-joining in SMARCB1-Deficient Tumors. https://doi.org/10.1101/2025.11.20.689563

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