2. Academic Validation
  3. Defective Microhomology-Mediated End-joining in SMARCB1-Deficient Tumors

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

  • bioRxiv. 2025 Nov 21:2025.11.20.689563. doi: 10.1101/2025.11.20.689563.
Guangli Zhu 1 2,  Shuhei Asada 1,  Huy Nguyen 1,  Yuna Hirohashi 1,  Lifang Sun 1,  Avneesh Saravanapavan 3,  Sirisha Mukkavalli 1,  Geoffrey I Shapiro 4 5,  Alan D D'Andrea 1 4 5
Affiliations

Affiliations

  • 1 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Duke University School of Medicine, Durham, NC, USA.
  • 4 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
PMID: 41332615 DOI: 10.1101/2025.11.20.689563
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.

Keywords

DNA double-strand break; Fanconi Anemia/BRCA Pathway; Microhomology-Mediated End-joining; Rhabdoid Tumor; SMARCB1.

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