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Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways
C Barlow1, K D Brown, C X Deng
1Laboratory of Genetic Disease Research, National Institute of Diabetes, Digestive and Kidney Disorders, Bethesda, Maryland 20892, USA.
Nature Genetics
|December 17, 1997
Summary
The ATM protein is crucial for DNA damage response, but its deficiency selectively impairs p53-dependent cell-cycle arrest, not apoptosis, after radiation exposure.
Area of Science:
- DNA damage response
- Cellular signaling pathways
- Radiation biology
Background:
- ATM is involved in the DNA damage response to ionizing radiation (IR).
- ATM-deficient cells and mice show defective p53 induction after IR.
- p53 regulates both cell-cycle progression and apoptosis, but the mechanisms of differential activation are unclear.
Purpose of the Study:
- To elucidate the relationship between ATM and p53 in response to IR.
- To investigate how ATM deficiency affects p53-mediated downstream pathways.
Main Methods:
- Examined cell-cycle and apoptotic responses in ATM-, p53-, and p21-deficient mice after IR.
- Analyzed p53 induction, p21 induction, and Bax induction in response to IR.
- Utilized Atm/p53 and Atm/p21 double-mutant mice to assess pathway dependence.
Main Results:
- ATM deficiency abolished IR-induced p53 and p21 induction in mouse thymus.
- ATM deficiency did not affect IR-induced apoptosis or Bax induction, which are p53-mediated.
- IR-induced thymic apoptosis was suppressed in Atm/p53 double mutants but not Atm/p21 double mutants.
Conclusions:
- ATM deficiency leads to a lack of p53 induction by IR.
- ATM selectively disrupts specific p53-dependent functions, impacting cell-cycle arrest but not apoptosis.
- ATM acts as an upstream effector that selectively activates p53 to regulate distinct downstream pathways.