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Molecular and Cellular Biology, March 2006, p. 1598-1609, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1598-1609.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

DNA Damage during Reoxygenation Elicits a Chk2-Dependent Checkpoint Response

Rachel A. Freiberg, Ester M. Hammond, Mary Jo Dorie, Scott M. Welford, and Amato J. Giaccia*

Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, California 94305-5152

Received 10 August 2005/ Returned for modification 4 October 2005/ Accepted 14 December 2005

Due to the abnormal vasculature of solid tumors, tumor cell oxygenation can change rapidly with the opening and closing of blood vessels, leading to the activation of both hypoxic response pathways and oxidative stress pathways upon reoxygenation. Here, we report that ataxia telangiectasia mutated-dependent phosphorylation and activation of Chk2 occur in the absence of DNA damage during hypoxia and are maintained during reoxygenation in response to DNA damage. Our studies involving oxidative damage show that Chk2 is required for G2 arrest. Following exposure to both hypoxia and reoxygenation, Chk2–/– cells exhibit an attenuated G2 arrest, increased apoptosis, reduced clonogenic survival, and deficient phosphorylation of downstream targets. These studies indicate that the combination of hypoxia and reoxygenation results in a G2 checkpoint response that is dependent on the tumor suppressor Chk2 and that this checkpoint response is essential for tumor cell adaptation to changes that result from the cycling nature of hypoxia and reoxygenation found in solid tumors.

* Corresponding author. Mailing address: CCSR South, Room 1255, Department of Radiation Oncology, Stanford University, Stanford, CA 94305-5152. Phone: (650) 723-7366. Fax: (650) 723-7382. E-mail: giaccia{at}leland.stanford.edu.

Molecular and Cellular Biology, March 2006, p. 1598-1609, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1598-1609.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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