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Defect in multiple cell cycle checkpoints in ataxia-telangiectasia postirradiation

H Beamish1, R Williams, P Chen

  • 1Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Road, Brisbane, Queensland 4029, Australia.

The Journal of Biological Chemistry
|August 23, 1996
PubMed

Insights

Ataxia-telangiectasia (A-T) cells exhibit resistant cyclin-dependent kinases to radiation, failing to induce WAF1. This cell cycle defect involves the ATM gene, impacting multiple cell cycle regulation points.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Ataxia-telangiectasia (A-T) is linked to mutations in the ATM gene, involved in cell cycle checkpoint control.
  • Cell cycle checkpoints, particularly G1/S and G2/M, are crucial for preventing genomic instability.
  • Cyclin-dependent kinases (CDKs) regulate cell cycle progression and are targets of checkpoint control.

Purpose of the Study:

  • To investigate the role of cyclin-dependent kinases (CDKs) in cell cycle control defects in A-T cells.
  • To determine if radiation-induced cell cycle inhibition is impaired in A-T cells.
  • To examine the involvement of WAF1 induction in radiation response in A-T and control cells.

Main Methods:

  • Irradiation of control and A-T lymphoblastoid cells during S and G2 phases.
  • Assay of cyclin A-Cdk2 and cyclin B-Cdc2 activities post-irradiation.
  • Quantification of Cdk-associated WAF1 levels before and after irradiation.

Main Results:

  • Control cells showed rapid inhibition of CDK activities (cyclin A-Cdk2, cyclin B-Cdc2) after irradiation, correlated with a 5-20 fold WAF1 increase.
  • A-T cells exhibited resistance to radiation-induced inhibition of CDK activities in both S and G2 phases.
  • No significant change in Cdk-associated WAF1 levels was observed in A-T cells following irradiation.

Conclusions:

  • A-T cells display impaired cell cycle regulation, with CDKs resistant to radiation-induced inhibition.
  • Insufficient WAF1 induction appears to be a key factor in the radioresistance of cell cycle checkpoints in A-T.
  • These findings support the involvement of the ATM gene in multiple cell cycle regulatory points, including G1/S and G2/M checkpoints.

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