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

Suhas S Kharat1, Arun P Mishra2, Satheesh K Sengodan2

  • 1Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA; Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA.

The Journal of Biological Chemistry
|June 21, 2025
PubMed

Insights

5-hydroxymethylcytosine (5hmC) can re-sensitize BRCA1/2-deficient cancer cells to PARP inhibitors like olaparib. This finding offers a new strategy to overcome drug resistance in hereditary breast and ovarian cancers.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Mutations in BRCA1 and BRCA2 genes are primary drivers of hereditary breast and ovarian cancers.
  • BRCA1/2-mutant cells exhibit DNA repair defects via homologous recombination and are sensitive to PARP inhibitors.
  • Drug resistance to PARP inhibitors presents a significant challenge in treating these cancers.

Purpose of the Study:

  • To investigate the role of 5-hydroxymethylcytosine (5hmC) in the efficacy of PARP inhibitors.
  • To explore mechanisms by which 5hmC might overcome PARP inhibitor resistance in BRCA1/2-deficient cells.

Main Methods:

  • Treatment of cells with olaparib, a PARP inhibitor.
  • Analysis of PARP1 trapping on chromatin.
  • Assessment of replication gap formation.
  • Evaluation of cellular sensitivity to PARP inhibitors in chemoresistant models.

Main Results:

  • 5-hydroxymethylcytosine (5hmC) was found to enhance PARP1 trapping on chromatin in olaparib-treated cells.
  • Increased PARP trapping led to the generation of replication gaps.
  • These effects restored sensitivity to PARP inhibitors in chemoresistant BRCA1/2-deficient cells.

Conclusions:

  • Combining 5hmC with olaparib can restore sensitivity to PARP inhibitors in chemoresistant BRCA1/2-deficient cancers.
  • This approach presents a potential therapeutic strategy to combat drug resistance in hereditary breast and ovarian cancers.
Keywords:
5hmCBRCA1BRCA2PARP inhibitorTET proteinschemoresistanceolaparibtalazoparibvitamin C

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