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Protective roles for ATM in cellular response to oxidative stress
1Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Abstract:
ATM (ataxia telangiectasia mutated), the gene mutated in ataxia telangiectasia, is related to a family of large phosphatidylinositol 3-kinase domain-containing proteins involved in cell cycle control and DNA repair. We found that ATM(-/-) DT40 cells were more susceptible than wild-type cells to apoptosis induced not only by ionizing radiation and bleomycin but also by non-DNA-damaging apoptotic stimuli such as C(2)-ceramide. Furthermore, the apoptosis induced by C(2)-ceramide and H(2)O(2) was blocked by anti-oxidants, indicating that the ATM(-/-) DT40 cells had a heightened susceptibility to apoptosis induced by reactive oxygen intermediates (ROI), presumably due to defective ROI-detoxification activities. In support of this hypothesis, we found that more ROI were generated in ATM(-/-) DT40 cells than in wild-type cells, following treatment with the above apoptotic stimuli. These results indicate that ATM plays important roles in the maintenance of the cell homeostasis in response to oxidative damage.
Insights
Ataxia telangiectasia mutated (ATM) protein deficiency increases susceptibility to cell death from oxidative stress. ATM-deficient cells show heightened apoptosis due to defective reactive oxygen intermediate detoxification.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- The ataxia telangiectasia mutated (ATM) gene encodes a protein kinase involved in DNA repair and cell cycle control.
- ATM is part of a family of phosphatidylinositol 3-kinase-related proteins.
- Mutations in ATM cause ataxia telangiectasia, a human genetic disorder.
Purpose of the Study:
- To investigate the role of ATM in cellular response to oxidative stress.
- To determine if ATM deficiency affects susceptibility to apoptosis induced by non-DNA-damaging agents.
Main Methods:
- Comparison of apoptosis induction in ATM-deficient (ATM-/-) DT40 cells versus wild-type DT40 cells.
- Treatment with DNA-damaging agents (ionizing radiation, bleomycin) and non-DNA-damaging agents (C(2)-ceramide, H(2)O(2)).
- Assessment of reactive oxygen intermediate (ROI) generation and the effect of antioxidants.
Main Results:
- ATM-/- DT40 cells exhibited increased susceptibility to apoptosis induced by both DNA-damaging and non-DNA-damaging stimuli.
- Antioxidants blocked C(2)-ceramide and H(2)O(2)-induced apoptosis in ATM-/- cells, suggesting heightened sensitivity to ROI.
- Elevated ROI generation was observed in ATM-/- cells compared to wild-type cells after apoptotic stimuli treatment.
Conclusions:
- ATM plays a crucial role in maintaining cellular homeostasis under conditions of oxidative damage.
- Defective ROI detoxification contributes to the increased apoptosis observed in ATM-deficient cells.
- ATM is essential for cellular defense against oxidative stress.