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Irreversible chromosome damage accumulates rapidly in the absence of ATM kinase activity

Jason S White1, Serah Choi, Christopher J Bakkenist

  • 1Department of Radiation Oncology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.

Cell Cycle (Georgetown, Tex.)
|April 18, 2008
PubMed

Insights

Transiently inhibiting ATM kinase activity after irradiation rapidly causes chromosomal instability in cells. This unexpected finding reveals ATM

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Ataxia telangiectasia (A-T) is a neurodegenerative disorder caused by mutations in ATM kinase.
  • A-T patients exhibit extreme radiation sensitivity and cancer predisposition due to chromosome aberrations and cellular radiosensitivity.
  • ATM kinase is crucial for cell cycle checkpoints and apoptosis induction post-irradiation, but these functions don't fully explain A-T chromosomal instability.

Purpose of the Study:

  • To investigate the role of ATM kinase activity inhibition in cellular radiosensitivity and chromosomal instability.
  • To determine the timing and extent of ATM kinase inhibition's impact on radiation-induced damage.
  • To explore a potential novel function of ATM kinase in maintaining genomic stability.

Main Methods:

  • Utilized the small molecule KU55933 as a selective and transient ATM kinase inhibitor.
  • Administered KU55933 for short (1 hour) and extended (17 hours) periods post-gamma-ray exposure.
  • Quantified cellular radiosensitization and counted chromosome aberrations in different cell cycle phases (late-S, G2, M).

Main Results:

  • Transient inhibition of ATM kinase activity for 1 hour post-irradiation accounted for over 70% of the radiosensitization observed with 17-hour inhibition.
  • Short-term ATM inhibition (1 hour) post-irradiation doubled chromosome aberrations in late-S and G2 phase cells, but not in M-phase cells.
  • Irreversible chromosome damage accumulates rapidly upon transient ATM kinase inhibition following irradiation.

Conclusions:

  • ATM kinase activity is essential for suppressing chromosomal instability, particularly in the immediate aftermath of irradiation.
  • Transient inhibition of ATM kinase is sufficient to induce significant radiosensitization and chromosomal aberrations.
  • This study uncovers a previously unrecognized role for ATM kinase in preventing rapid accumulation of irreversible DNA damage.

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