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Targeting ZDHHC12-mediated PARP1 palmitoylation potentiates PARP inhibitor cytotoxicity

Xining Zhang1, Ye Liu2, Xingming Liao3

  • 1Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China.

Cell Reports
|January 25, 2026
PubMed

Insights

Reversible S-palmitoylation regulates Poly(ADP-ribose) polymerase inhibitors (PARPi) by affecting PARP1 chromatin binding. Inhibiting ZDHHC12-mediated PARP1 palmitoylation overcomes PARPi resistance in ovarian cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are crucial for cancer therapy by trapping PARP1 at DNA damage sites.
  • Clinical resistance to PARPi remains a significant hurdle in treating cancers like high-grade serous ovarian cancer (HGSOC).

Purpose of the Study:

  • To investigate the role of protein post-translational modifications in regulating PARP1 function and PARPi response.
  • To identify novel targets for overcoming PARPi resistance.

Main Methods:

  • Mass spectrometry to identify and localize PARP1 palmitoylation.
  • In vitro assays to assess PARP1 DNA binding and trapping.
  • Cellular and xenograft models of HGSOC to evaluate drug sensitivity.
  • Genetic manipulation of palmitoyltransferases and depalmitoylases.

Main Results:

  • PARP1 undergoes reversible S-palmitoylation at conserved cysteines in its DNA-binding domains.
  • DNA damage decreases PARP1 palmitoylation, enhancing its chromatin engagement.
  • The palmitoyltransferase ZDHHC12 catalyzes PARP1 palmitoylation; its inhibition enhances PARP1 trapping and sensitizes HGSOC cells to Niraparib.
  • Patient-derived PARP1 variants exhibit resistance via a mechanism independent of direct mutation site palmitoylation.

Conclusions:

  • Reversible S-palmitoylation acts as a negative regulator of PARP1 chromatin engagement.
  • ZDHHC12-mediated PARP1 palmitoylation is a targetable vulnerability to overcome PARPi resistance in HGSOC.
  • Targeting ZDHHC12 offers a potential strategy to resensitize resistant tumors to PARPi therapy.
Keywords:
CP: cancerCP: molecular biologyDNA damageNiraparibPARP inhibitorPARP1 palmitoylationPARP1 trappingZDHHC12ovarian cancer

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