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Early-stage apoptosis is associated with DNA-damage-independent ATM phosphorylation and chromatin decondensation in

Kenneth Bødtker Schou1, Linda Schneider, Søren Tvorup Christensen

  • 1Department of Molecular Biology, Section of Cellular and Devolopmental Biology, August Krogh Building, University of Copenhagen, Universitetsparken 15, DK-2100 Copenhagen OE, Denmark.

Cell Biology International
|October 20, 2007
PubMed

Insights

Early apoptosis involves chromatin decondensation and ataxia telangiectasia mutated (ATM) activation before DNA fragmentation. This suggests ATM activation occurs independently of DNA damage signaling pathways during initial apoptotic stages.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Apoptosis is characterized by chromatin condensation and DNA fragmentation.
  • Phosphorylation of ataxia telangiectasia mutated (ATM) and histone H2A.X occurs during apoptosis.
  • Previous studies indicated ATM and H2A.X phosphorylation coincide with DNA fragmentation.

Purpose of the Study:

  • To investigate the temporal relationship between ATM phosphorylation, chromatin decondensation, and DNA fragmentation during apoptosis.
  • To determine if ATM activation precedes DNA fragmentation and is independent of DNA damage signaling.

Main Methods:

  • Immunofluorescence microscopy
  • Western blot analysis
  • Alkali comet assays
  • Treatment of NIH3T3 fibroblasts with staurosporine (STS) or TNF-alpha/CHX.

Main Results:

  • ATM phosphorylation was observed to precede apoptotic DNA fragmentation, nuclease degradation, and histone H2A.X phosphorylation.
  • ATM activation was associated with chromatin decondensation, including the loss of dense heterochromatin foci.
  • These events occurred in cells treated with low levels of STS or TNF-alpha/CHX.

Conclusions:

  • ATM activation and chromatin decondensation occur independently of DNA damage signaling pathways in the early stages of apoptosis.
  • ATM phosphorylation is an early event in apoptosis, preceding DNA fragmentation.

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