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Chromosomal breaks during mitotic catastrophe trigger γH2AX-ATM-p53-mediated apoptosis

Gabriela Imreh1, Helin Vakifahmetoglu Norberg, Stefan Imreh

  • 1Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.

Journal of Cell Science
|September 1, 2011
PubMed

Insights

The γH2AX-ATM-p53 pathway regulates cell death during mitotic catastrophe (MC). DNA damage accumulation during MC triggers this pathway, influencing whether cells undergo apoptosis or necrosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Mitotic catastrophe (MC) is a form of cell death following mitosis.
  • The precise regulation of cell death during MC and the involved signaling pathways remain unclear.
  • Understanding cell death modality decisions after MC is crucial.

Purpose of the Study:

  • To elucidate the role of the γH2AX-ATM-p53 pathway in regulating apoptotic outcomes during MC.
  • To investigate the signaling mechanisms governing cell death decisions following MC.
  • To identify factors influencing the shift between apoptosis and necrosis in MC.

Main Methods:

  • Investigated the γH2AX-ATM-p53 pathway in cells entering mitosis with damaged DNA.
  • Utilized p53-deficient and ATM-depleted cell models.
  • Analyzed chromosomal damage, mitotic exit, and cell death modalities (apoptosis vs. necrosis).
  • Examined the role of 14-3-3σ in response to doxorubicin treatment.

Main Results:

  • The γH2AX-ATM-p53 pathway is critical for apoptotic cell death in MC.
  • ATM depletion, but not ATR depletion, protected against apoptosis and promoted necrosis.
  • Activation of the pathway is linked to increased chromosomal damage during anaphase.
  • Defects in mitotic exit and p53/p21-dependent cell cycle arrest occur in cells with abnormal chromosomes.
  • Extensive H2AX phosphorylation correlates with catastrophic mitosis and subsequent cell elimination.

Conclusions:

  • The γH2AX-ATM-p53 pathway dictates the apoptotic fate during MC.
  • Cellular response to DNA damage during mitosis involves a balance between apoptosis and necrosis.
  • MC can generate additional DNA damage to eliminate chromosomally unstable cells, highlighting a self-regulatory mechanism.

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