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Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells

Nicola Lockwood1, Silvia Martini1, Ainara Lopez-Pardo1

  • 1Protein Phosphorylation Laboratory, The Francis Crick Institute, 1 Midland Road, London, UK.

Cancer Research
|March 5, 2022
PubMed

Insights

Topoisomerase 2a (Topo2a) inhibition triggers G2 arrest, crucial for cell division. In cancer cells with faulty arrest, a PKCε-dependent pathway acts as a failsafe, offering therapeutic potential.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Topoisomerase 2a (Topo2a)-dependent G2 arrest ensures accurate sister chromatid segregation.
  • Dysfunctional Topo2a-mediated G2 arrest in tumor cells can activate a PKCε-dependent failsafe pathway.
  • Understanding these arrest mechanisms is key to developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the mechanisms of Topo2a-dependent G2 arrest and associated failsafe pathways.
  • To investigate the role of p53-p21 signaling and the SMC5/6 complex in Topo2a-induced G2 arrest.
  • To explore the distinct Topo2a-dependent G2 arrest in ALT-positive cancer cells and the engagement of the PKCε failsafe.

Main Methods:

  • Analysis of p53-p21 signaling in various cell lines, patient-derived cells, and colorectal cancer organoids.
  • Investigation of Topo2a inhibition during S phase and its effect on G2 arrest.
  • Characterization of Topo2a-dependent, p53-independent G2 arrest mediated by BLM and Chk1 in ALT cells.
  • Assessment of the PKCε-dependent failsafe in hTERT-positive cells with dysfunctional Topo2a arrest and absent p53.
  • Evaluation of tumor aggressiveness and chromosomal rearrangements in PKCε knockout mice with p53 deletion.

Main Results:

  • p53-p21 signaling, regulated by the SMC5/6 complex, is essential for efficient Topo2a-dependent G2 arrest.
  • Topo2a inhibition during S phase does not induce G2 arrest.
  • A distinct p53-independent G2 arrest mediated by BLM and Chk1 occurs in ALT cells.
  • The PKCε failsafe pathway is activated in hTERT-positive cells with absent p53 and dysfunctional Topo2a arrest, but not in ALT cells.
  • PKCε deficiency reduces tumor aggressiveness and alters chromosomal rearrangements in p53-deleted mice.

Conclusions:

  • p53-p21 signaling is critical for Topo2a-dependent G2 arrest, with regulation by the SMC5/6 complex.
  • Cancer cells employ distinct mechanisms for Topo2a-dependent G2 arrest, including p53-dependent and p53-independent pathways.
  • The PKCε-dependent failsafe pathway is specifically activated in hTERT-positive, arrest-defective tumors lacking p53.
  • Targeting PKCε offers a potential synthetic lethality strategy for arrest-defective hTERT-positive tumors.

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