An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells

Induction of checkpoint responses in G(1), S, and G(2) 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 G(2) arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G(2)-checkpoint response remains unknown. We report here that the G(2) checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G(2) checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G(2) arrest in AT cells and show that activation of this G(2) checkpoint contributes to the survival of AT cells.