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WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Kamila Burdova1, Radka Storchova2, Matous Palek3

  • 1Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, CZ14220 Prague, Czech Republic. kamila.burdova@img.cas.cz.

Cells
|October 18, 2019
PubMed

Insights

Protein phosphatase 2C delta (WIP1) promotes DNA repair via homologous recombination. Inhibiting WIP1 enhances DNA damage accumulation and cancer cell sensitivity to olaparib, particularly in BRCA1-proficient cells.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Genotoxic stress activates DNA repair and cell cycle checkpoints.
  • Protein phosphatase 2C delta (WIP1) normally inactivates DNA damage response pathways.
  • WIP1's role in DNA repair dynamics was previously unclear.

Purpose of the Study:

  • To investigate WIP1's role in DNA repair mechanisms.
  • To identify WIP1 interactors and substrates involved in DNA damage response.
  • To evaluate the therapeutic potential of WIP1 inhibition in cancer treatment.

Main Methods:

  • Analysis of DNA repair foci dynamics after ionizing radiation.
  • Identification of protein-protein interactions using co-immunoprecipitation.
  • Assessment of protein dephosphorylation events.
  • Cell viability assays and drug sensitivity testing.

Main Results:

  • WIP1 promotes DNA repair through homologous recombination.
  • Loss of WIP1 delays the resolution of 53BP1 foci and increases cell death.
  • Breast cancer associated protein 1 (BRCA1) is a WIP1 substrate, and WIP1 regulates BRCA1 chromatin recruitment.
  • WIP1 dephosphorylates 53BP1 at Threonine 543, affecting its interaction with RIF1.
  • WIP1 inhibition leads to DNA damage accumulation and sensitizes cancer cells to olaparib.

Conclusions:

  • WIP1 plays a crucial role in regulating DNA repair dynamics.
  • WIP1 inhibition represents a potential strategy to enhance the efficacy of PARP inhibitors like olaparib in BRCA1-proficient cancers.
Keywords:
DNA repairPARP inhibitorchemotherapygenotoxic stressolaparibphosphatase

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