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TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

Pavel Moudry1, Kenji Watanabe2, Kamila M Wolanin2

  • 1Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic.

The Journal of Cell Biology
|January 27, 2016
PubMed

Insights

Topoisomerase IIβ-binding protein 1 (TOPBP1) is crucial for homologous recombination DNA repair. Loss of TOPBP1 sensitizes cancer cells to olaparib, offering potential new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Topoisomerase IIβ-binding protein 1 (TOPBP1) is involved in DNA replication and damage response.
  • Its specific role in DNA repair and significance in human cancers are not fully understood.

Purpose of the Study:

  • To investigate the role of TOPBP1 in DNA repair pathways.
  • To determine the relevance of TOPBP1 in human cancer, particularly in response to olaparib treatment.

Main Methods:

  • Utilized an unbiased small interfering RNA screen to identify genes affecting olaparib sensitivity.
  • Assessed TOPBP1's function in homologous recombination (HR) repair by examining RAD51 loading and foci formation.
  • Investigated the interaction between TOPBP1, PLK1, and RAD51 phosphorylation.

Main Results:

  • TOPBP1 was identified as a novel determinant sensitizing cells to olaparib (a PARP inhibitor).
  • TOPBP1 depletion impaired RAD51 chromatin loading and foci formation, crucial steps in HR repair.
  • TOPBP1 physically interacts with PLK1, promoting RAD51 phosphorylation at serine 14, essential for its chromatin recruitment.
  • Aberrant TOPBP1 patterns were observed in subsets of human ovarian carcinomas.

Conclusions:

  • TOPBP1 plays a critical role in homologous recombination repair by facilitating RAD51 recruitment.
  • TOPBP1's function in HR repair and its aberrant expression in ovarian cancer suggest potential clinical implications for cancer therapy.

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