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J. Biol. Chem., Vol. 278, Issue 33, 30869-30874, August 15, 2003

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

Xiang Wang , Jay Khadpe , Baocheng Hu , George Iliakis  and Ya Wang  ¶

From the Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the Institute of Medical Radiation Biology, University of Essen Medical School, 45122 Essen, Germany

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.

Received for publication, February 21, 2003 , and in revised form, May 30, 2003.

^* This work was supported by NASA Grant NAG2-1628, National Institutes of Health Grants CA76203 (to Y. W.), CA42026 and CA56706 (to G. I.), as well as R25 CA48010 and P30-CA56036. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Thomas Jefferson University, Thompson Bldg., B1, 1020 Sansom St., Philadelphia, PA 19107. Tel.: 215-955-2045; Fax: 215-955-2052; E-mail: ya.wang{at}mail.tju.edu.

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