5hmC enhances PARP trapping and restores PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells

Author:

Kharat, Suhas S

Mishra,Arun

Sengodan,Satheesh

Dierman, Dillon

Fox, Stephen D

Chazin, Walter J

Sharan,Shyam
Author Address

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702 USA; Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702 USA., Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702 USA. Electronic address: sharans@mail.nih.gov.,

Abstract:

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 in spite of 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 sensitivity in chemoresistant BRCA1/2-deficient cells. Our findings suggest that combining 5hmC with olaparib can restore the sensitivity of chemoresistant BRCA1/2-deficient cells. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

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