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PARP inhibition causes premature loss of cohesion in cancer cells

Eva Kukolj1, Tanja Kaufmann1, Amalie E Dick2

  • 1Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, Vienna, Austria.

Oncotarget
|December 22, 2017
PubMed

Insights

Poly(ADP-ribose) polymerases (PARPs) inhibition disrupts mitosis, causing sister chromatid scattering in cancer cells. This occurs when PARP inhibitors like olaparib engage PARP1/2 during S-phase, impairing replication and cohesion.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Poly(ADP-ribose) polymerases (PARPs) are crucial for DNA repair and mitotic progression.
  • PARP inhibitors, such as olaparib, are used in cancer therapy, but their precise anti-tumor mechanisms, particularly concerning mitosis, require further elucidation.
  • Understanding PARP inhibitor effects on cell division is vital for optimizing cancer treatment strategies.

Purpose of the Study:

  • To investigate the impact of PARP inhibition on mitosis in various cancer and non-cancerous cell types.
  • To determine the role of PARP1 and PARP2 protein levels and catalytic activity in olaparib-induced mitotic defects.
  • To explore the relationship between replication stress and mitotic aberrations caused by PARP inhibition.

Main Methods:

  • Live-cell imaging was employed to observe mitotic progression in cancer and non-cancer cells treated with olaparib.
  • PARP1 and PARP2 gene expression levels were manipulated (depletion and overexpression) to assess their influence on observed phenotypes.
  • Cells were treated with olaparib during different cell cycle phases (S-phase vs. other phases) to pinpoint the timing of critical events.

Main Results:

  • Olaparib induced significant mitotic perturbations, including chromosome misalignment, anaphase delay, and sister chromatid scattering due to cohesion fatigue.
  • PARP1/2 depletion reversed these defects, while PARP2 overexpression exacerbated them, indicating that olaparib-bound PARP1/2, not just catalytic inactivity, drives the phenotype.
  • The sister chromatid scattering phenotype was prominent in cancer cells with high PARP1/2 levels and occurred specifically when olaparib was administered during S-phase, suggesting replication fork trapping.
  • Replication-perturbing agents like topoisomerase inhibitors and cisplatin mimicked these mitotic issues, highlighting a common pathway.

Conclusions:

  • PARP inhibition by olaparib causes mitotic errors, specifically sister chromatid scattering, by trapping PARP1/2 at replication forks during S-phase, thereby compromising sister chromatid cohesion.
  • The observed mitotic defects are dependent on the levels of PARP1 and PARP2 and are linked to replication stress, suggesting a broader implication for DNA-damaging chemotherapies.
  • These findings provide critical insights into the mode of action of PARP inhibitors and their impact on cancer cell division.
Keywords:
PARP entrapmentPARP inhibitorscohesionlive-cell imagingmitosis

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