Data from SMARCA4 Loss Increases RNA Polymerase II Pausing and Elevates R-Loops to Inhibit BRCA1-Mediated Repair in Ovarian Cancer

<div>Abstract<p>Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women driven by inactivating mutations in <i>SMARCA4</i>, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits despite retaining wild-type BRCA1 expression. Elevated R-loop in SCCOHT sequestered BRCA1, limiting its availability for DNA damage repair. Proximity-dependent biotin identification revealed that wild-type SMARCA4, but not its pathogenic variants, promoted RNA polymerase II (Pol II) elongation by mediating the assembly of the polymerase-associated factor 1 complex. Thus, SMARCA4 loss increased Pol II pausing, resulting in elevated R-loops and BRCA1 redistribution. The suppression of BRCA1 activity sensitized SMARCA4-deficient SCCOHT cells and tumors to PARP inhibitors, which was further enhanced by the addition of a CDK9 inhibitor targeting Pol II elongation. Cotargeting PARP/CDK9 also elicited synergistic effects against other undifferentiated ovarian cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and other SWI/SNF-deficient ovarian cancers.</p>Significance:<p>Pol II stalling induced by SMARCA4 loss leads to R-loop accumulation that sequesters BRCA1 to transcription complexes, underlying the sensitivity of SMARCA4-deficient ovarian cancers to inhibitors targeting PARPs and Pol II elongation.</p></div>

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Publication Details

Published
2025-08-15
DOI
https://doi.org/10.1158/0008-5472.c.7983475
Citations
1
Primary Topic
Chromatin Remodeling and Cancer
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article
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0.81
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article

Data from SMARCA4 Loss Increases RNA Polymerase II Pausing and Elevates R-Loops to Inhibit BRCA1-Mediated Repair in Ovarian Cancer

Zheng Fu, Virginie Pilon, W. Glenn McCluggage, Yibo Xue et al.
1 citations
Chromatin Remodeling and Cancer
0.81
article

Data from SMARCA4 Loss Increases RNA Polymerase II Pausing and Elevates R-Loops to Inhibit BRCA1-Mediated Repair in Ovarian Cancer

Zheng Fu, Virginie Pilon, W. Glenn McCluggage, Yibo Xue, Anie Monast, Alexander J.R. Bishop, Giulio Aceto, Walter H. Gotlieb, William D. Foulkes, Azadeh Arabzadeh, Xianbing Zhu, Douglas A. Levine, Alica Valachová, Brian Raught, Kitty Pavlakis, Sidong Huang, Amber Yasmeen, Jonathan St‐Germain, Leora Witkowski, Geneviève Morin, Jingjie Guo, Nicklas Bassani, Jutta Steinberger, David G. Huntsman, Yemin Wang, Morag Park, Selim Mısırlıoğlu, Yuxuan Qi, Lili Fu, K Liu, Elise Graulich, Racim Sansal
article en
1 citations

Abstract

<div>Abstract<p>Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women driven by inactivating mutations in <i>SMARCA4</i>, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits despite retaining wild-type BRCA1 expression. Elevated R-loop in SCCOHT sequestered BRCA1, limiting its availability for DNA damage repair. Proximity-dependent biotin identification revealed that wild-type SMARCA4, but not its pathogenic variants, promoted RNA polymerase II (Pol II) elongation by mediating the assembly of the polymerase-associated factor 1 complex. Thus, SMARCA4 loss increased Pol II pausing, resulting in elevated R-loops and BRCA1 redistribution. The suppression of BRCA1 activity sensitized SMARCA4-deficient SCCOHT cells and tumors to PARP inhibitors, which was further enhanced by the addition of a CDK9 inhibitor targeting Pol II elongation. Cotargeting PARP/CDK9 also elicited synergistic effects against other undifferentiated ovarian cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and other SWI/SNF-deficient ovarian cancers.</p>Significance:<p>Pol II stalling induced by SMARCA4 loss leads to R-loop accumulation that sequesters BRCA1 to transcription complexes, underlying the sensitivity of SMARCA4-deficient ovarian cancers to inhibitors targeting PARPs and Pol II elongation.</p></div>

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