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Dual roles of ATM in the cellular response to radiation and in cell growth control

Y Xu1, D Baltimore

  • 1Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.

Genes & Development
|October 1, 1996
PubMed

Insights

Mice lacking the ATM gene show sensitivity to radiation and cell cycle defects, mirroring ataxia-telangiectasia (AT) patient cellular issues. This highlights ATM

Area of Science:

  • Genetics
  • Cell Biology
  • Cancer Research

Background:

  • Ataxia-telangiectasia (AT) is a genetic disorder linked to mutations in the ATM gene.
  • The ATM gene encodes a protein kinase crucial for cellular functions.
  • Understanding ATM's role is vital for AT patient treatment and cancer research.

Purpose of the Study:

  • To investigate the function of the ATM gene and its protein product.
  • To create and analyze a mouse model with a disrupted ATM gene (ATM-/-).
  • To understand the cellular consequences of ATM deficiency.

Main Methods:

  • Homologous recombination was used to disrupt the mouse ATM gene.
  • ATM-/- cells were analyzed for sensitivity to gamma-irradiation.
  • Cell-cycle progression, apoptosis, and p53/p21 protein levels were assessed in ATM-/- cells and fibroblasts.

Main Results:

  • ATM-/- cells exhibited hypersensitivity to gamma-irradiation and defective cell-cycle arrest.
  • A correlation was observed between defective p53 up-regulation and radiation response.
  • ATM-/- fibroblasts showed impaired G1 to S-phase progression and premature senescence.
  • ATM-/- thymocytes were more resistant to radiation-induced apoptosis.
  • ATM+/- cells displayed intermediate radiation sensitivity without growth defects.

Conclusions:

  • The ATM protein is essential for cellular responses to ionizing radiation and normal cell-cycle progression.
  • Defective checkpoint function in ATM heterozygotes may contribute to increased cancer risk.
  • This study provides critical insights into ATM's role in DNA damage response and cell fate.

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