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Ionizing radiation activates the ATM kinase throughout the cell cycle
T K Pandita1, H B Lieberman, D S Lim
1Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Abstract:
The ATM protein kinase is a critical intermediate in a number of cellular responses to ionizing irradiation (IR) and possibly other stresses. ATM dysfunction results in abnormal checkpoint responses in multiple phases of the cell cycle, including G1, S and G2. Though downstream targets of the ATM kinase are still being elucidated, it has been demonstrated that ATM acts upstream of p53 in a signal transduction pathway initiated by IR and can phosphorylate p53 at serine 15. The cell cycle stage-specificity of ATM activation and p53Ser15 phosphorylation was investigated in normal lymphoblastoid cell line (GM536). Ionizing radiation was found to enhance the kinase activity of ATM in all phases of the cell cycle. This enhanced activity was apparent immediately after treatment of cells with IR, but was not accompanied by a change in the abundance of the ATM protein. Since IR activates the ATM kinase in all phases of the cell cycle, DNA replication-dependent strand breaks are not required for this activation. Further, since p53 protein is not directly required for IR-induced S and G2-phase checkpoints, the ATM kinase likely has different functional targets in different phases of the cell cycle. These observations indicate that the ATM kinase is necessary primarily for the immediate response to DNA damage incurred in all phases of the cell cycle.
Insights
The ATM protein kinase responds to ionizing radiation (IR) in all cell cycle phases. This DNA damage response is immediate and does not require DNA replication-dependent strand breaks or p53 protein.
Area of Science:
- Cellular biology
- Molecular oncology
- DNA damage response
Background:
- The ATM (ataxia-telangiectasia mutated) protein kinase is a key regulator of cellular responses to DNA damage, particularly from ionizing radiation (IR).
- ATM dysfunction leads to cell cycle checkpoint failures in G1, S, and G2 phases.
- ATM acts upstream of p53, phosphorylating it at serine 15 in response to IR.
Purpose of the Study:
- To investigate the cell cycle stage-specificity of ATM activation and p53Ser15 phosphorylation.
- To determine if DNA replication-dependent strand breaks are required for ATM activation.
- To explore the role of p53 in ATM-mediated cell cycle checkpoints.
Main Methods:
- Utilized a normal lymphoblastoid cell line (GM536).
- Exposed cells to ionizing radiation (IR) at different cell cycle phases.
- Assessed ATM kinase activity and p53Ser15 phosphorylation levels.
Main Results:
- Ionizing radiation enhanced ATM kinase activity across all cell cycle phases (G1, S, and G2).
- Enhanced ATM activity was observed immediately post-IR, without changes in ATM protein levels.
- ATM activation by IR does not depend on DNA replication-dependent strand breaks.
- p53 protein is not essential for IR-induced S and G2-phase checkpoints, suggesting ATM has phase-specific targets.
Conclusions:
- The ATM kinase is crucial for the immediate cellular response to DNA damage induced by IR in all cell cycle phases.
- ATM activation is independent of DNA replication status and p53 in response to IR.
- ATM likely targets different proteins in distinct cell cycle phases to execute its functions.