An Overactivated ATR/CHK1 Pathway Is Responsible for the Prolonged G2 Accumulation in Irradiated AT Cells

Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. Howev...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-08, Vol.278 (33), p.30869-30874
Main Authors: Wang, Xiang, Khadpe, Jay, Hu, Baocheng, Iliakis, George, Wang, Ya
Format: Article
Language:English
Subjects:
Alkaloids - pharmacology
Ataxia Telangiectasia Mutated Proteins
Caffeine - pharmacology
Cell Cycle Proteins - antagonists & inhibitors
Cell Cycle Proteins - metabolism
Cell Line, Transformed
Cell Survival - physiology
Cell Survival - radiation effects
Checkpoint Kinase 1
Enzyme Inhibitors - pharmacology
Fibroblasts - cytology
Fibroblasts - metabolism
Fibroblasts - radiation effects
G2 Phase - physiology
G2 Phase - radiation effects
Humans
Life Sciences (General)
Phosphodiesterase Inhibitors - pharmacology
Protein Kinase Inhibitors
Protein Kinases - genetics
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases
Radiation, Ionizing
RNA, Small Interfering
Space life sciences
Staurosporine - analogs & derivatives
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Summary:Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. However, cells lacking functional ATM exhibit a prolonged G2 arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G2-checkpoint response remains unknown. We report here that the G2 checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G2 checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G2 arrest in AT cells and show that activation of this G2 checkpoint contributes to the survival of AT cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M301876200