Defective microhomology-mediated end joining in <i>SMARCB1</i> -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.

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Publication Details

Journal
Science Advances
Published
2026-08-14
DOI
https://doi.org/10.1126/sciadv.aed7743
Primary Topic
Chromatin Remodeling and Cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Defective microhomology-mediated end joining in SMARCB1 -deficient tumors

Huy Nguyen, Sirisha Mukkavalli, Yuna Hirohashi, Alan D. D’Andrea et al.
Science Advances
Chromatin Remodeling and Cancer
article

Defective microhomology-mediated end joining in SMARCB1 -deficient tumors

Huy Nguyen, Sirisha Mukkavalli, Yuna Hirohashi, Alan D. D’Andrea, Geoffrey Ira Shapiro, Guang‐Li Zhu, Shuhei Asada, Mona Batish, Lifang Sun, Erfan Rahmani, Avneesh Saravanapavan, Maryia Hrynashka
article en

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, 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.

Science AdvancesVol. 12(33)
Harvard University (US), Sun Yat-sen University (CN), Duke University (US), Dana-Farber Cancer Institute (US), The First Affiliated Hospital, Sun Yat-sen University (CN), University of Delaware (US)
National Science Foundation, Breast Cancer Research Foundation, SENSHIN Medical Research Foundation, National Institutes of Health, Ludwig Center at Harvard, Japan Society for the Promotion of Science
Good health and well-being
Openalex Percentile: Top 16%
Chromatin Remodeling and Cancer
DOIOpen Access PDFOpenAlex
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