Reference - Detail
| RRC ID | 86337 |
|---|---|
| Author | Zhu X, Fu Z, Aceto G, St-Germain J, Liu K, Arabzadeh A, Qi Y, Xue Y, Witkowski L, Graulich E, Steinberger J, Misirlioglu S, Bassani N, Sansal R, Yasmeen A, Morin G, Guo J, Monast A, Pilon V, Valachová A, Pavlakis K, Fu L, Gotlieb WH, McCluggage WG, Huntsman D, Bishop AJR, Levine DA, Park M, Wang Y, Raught B, Foulkes WD, Huang S. |
| Title | SMARCA4 Loss Increases RNA Polymerase II Pausing and Elevates R-Loops to Inhibit BRCA1-Mediated Repair in Ovarian Cancer. |
| Journal | Cancer Res |
| Abstract |
UNLABELLED:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women driven by inactivating mutations in SMARCA4, 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. SIGNIFICANCE: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. |
| Volume | 85(16) |
| Pages | 2997-3014 |
| Published | 2025-8-15 |
| DOI | 10.1158/0008-5472.CAN-24-3990 |
| PII | 762423 |
| PMID | 40366633 |
| MeSH | Animals BRCA1 Protein* / genetics BRCA1 Protein* / metabolism Cell Line, Tumor DNA Helicases* / genetics DNA Helicases* / metabolism DNA Repair* Female Humans Mice Nuclear Proteins* / genetics Nuclear Proteins* / metabolism Ovarian Neoplasms* / drug therapy Ovarian Neoplasms* / genetics Ovarian Neoplasms* / metabolism Ovarian Neoplasms* / pathology Poly(ADP-ribose) Polymerase Inhibitors / pharmacology RNA Polymerase II* / genetics RNA Polymerase II* / metabolism Transcription Factors* / genetics Transcription Factors* / metabolism Xenograft Model Antitumor Assays |
| IF | 9.727 |
| Resource | |
| Human and Animal Cells | OVK18(RCB1903) |