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A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation

Lili Cao1, Hidehiko Kawai2, Megumi Sasatani3

  • 1Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Plos One
|August 6, 2014
PubMed

Insights

Chronic gamma irradiation causes more cellular senescence than acute exposure, particularly in fibroblasts. The ATM/TP53/p21 pathway is critical for this DNA damage response and cell fate determination.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Radiation Biology

Background:

  • DNA damage triggers various cellular responses like cell-cycle arrest, repair, senescence, and apoptosis.
  • Mechanisms governing cell-fate decisions after DNA damage are not fully understood.

Purpose of the Study:

  • To investigate how different doses and dose rates of gamma irradiation affect cell-type-specific responses.
  • To elucidate the mechanisms of cell-fate determination in response to varying DNA damage rates.

Main Methods:

  • Exposure of cultured cells and mice to different doses and dose rates of gamma irradiation.
  • Analysis of cell-type-specific sensitivities, cell-cycle arrest, and senescence.
  • Investigation of the role of the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway.

Main Results:

  • Chronic gamma irradiation induced higher levels of cellular senescence compared to acute exposure, especially in human fibroblasts.
  • Fibroblasts showed cell-type-specific sensitivity to chronic irradiation, exhibiting reversible G1 arrest or irreversible senescence.
  • The ATM/TP53/p21 pathway was crucial; its blockade led to deregulated DNA damage responses and micronucleus formation.

Conclusions:

  • The rate of DNA damage significantly influences cell-fate decisions, with chronic exposure promoting senescence.
  • The ATM/TP53/p21 pathway plays a critical role in mediating these differential responses to DNA damage.
  • Findings provide insights into the mechanisms of cell-fate determination under varying DNA damage conditions.

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