biostudies-literatureKharat SSNational Institutes of Health National Cancer InstituteNIH110393https://www.ebi.ac.uk/biostudies/studies/S-EPMC12281170biostudies-literatureUnknown301(7)Mutations in BRCA1 and BRCA2 genes are the leading cause of hereditary breast and ovarian cancer. BRCA1/2-mutant cells are defective in repairing damaged DNA by homologous recombination and are characterized by hypersensitivity to PARP inhibitors. PARP inhibitors can trap PARP proteins on the chromatin, a mechanism that can contribute to the death of BRCA1/2-deficient cells. The FDA has approved multiple PARP inhibitors for the treatment of metastatic breast and ovarian cancers, yet despite the success of PARP inhibitors in treating BRCA1/2-mutant cancers, drug resistance is a major challenge. Here, we report that 5hmC enhances PARP1 trapping on the chromatin in olaparib-treated cells. Elevated PARP trapping generates replication gaps, leading to the restoration of PARP inhibitor sensitiviThe Journal of biological chemistry5hmC enhances PARP trapping and restores PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells.PMC12281170R01 CA218315Fox SDMishra APKharat SSDierman DSengodan SKChazin WJSharan SKfalse5hmC enhances PARP trapping and restores PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells.Mutations in BRCA1 and BRCA2 genes are the leading cause of hereditary breast and ovarian cancer. BRCA1/2-mutant cells are defective in repairing damaged DNA by homologous recombination and are characterized by hypersensitivity to PARP inhibitors. PARP inhibitors can trap PARP proteins on the chromatin, a mechanism that can contribute to the death of BRCA1/2-deficient cells. The FDA has approved multiple PARP inhibitors for the treatment of metastatic breast and ovarian cancers, yet despite the success of PARP inhibitors in treating BRCA1/2-mutant cancers, drug resistance is a major challenge. Here, we report that 5hmC enhances PARP1 trapping on the chromatin in olaparib-treated cells. Elevated PARP trapping generates replication gaps, leading to the restoration of PARP inhibitor sensitivi2025-01-01T00:00:00Z2025 Jun2026-03-16T07:07:36.334Z2025-08-17T03:05:47.226ZS-EPMC122811704054358410.1016/j.jbc.2025.110393