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Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction

James D Orth1, Alexander Loewer, Galit Lahav

  • 1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. james_orth@hms.harvard.edu

Molecular Biology of the Cell
|December 16, 2011
PubMed

Insights

Antimitotic drugs cause DNA damage and p53 induction by partially activating apoptosis during prolonged mitotic arrest. This partial activation of caspase-activated DNase (CAD) leads to DNA damage after cells exit mitosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Antimitotic drugs induce mitotic arrest, potentially leading to apoptosis, cell cycle arrest, or DNA damage.
  • The precise relationship between mitotic arrest, DNA damage, and apoptosis induction remains incompletely understood.

Purpose of the Study:

  • To investigate the mechanisms underlying DNA damage and p53 induction following prolonged mitotic arrest induced by antimitotic drugs.
  • To elucidate the role of caspases and caspase-activated DNase (CAD) in mediating these cellular responses.

Main Methods:

  • Live, single-cell imaging of human cancer cells treated with antimitotic drugs.
  • Assessing DNA damage, p53 induction, and caspase activation.
  • Utilizing caspase inhibitors and stable expression of a dominant-negative inhibitor of caspase-activated DNase (ICAD).

Main Results:

  • Prolonged mitotic arrest led to p53 induction after cells entered the G1 phase.
  • DNA damage was detected late in mitotic arrest and after cell cycle slippage.
  • Inhibition of caspases or CAD activation significantly reduced both DNA damage and p53 induction.
  • DNA damage occurred independently of full cytochrome C release, indicating partial apoptotic pathway activation.

Conclusions:

  • Prolonged mitotic arrest partially activates the apoptotic pathway, leading to the partial activation of CAD.
  • This partial CAD activation results in limited DNA damage and subsequent p53 induction after cells exit mitosis.
  • Caspase and CAD-mediated DNA damage may be a key mechanism of antimitotic drug action and could explain DNA damage from other cellular stresses.

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