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J. Biol. Chem., Vol. 279, Issue 11, 9677-9680, March 12, 2004
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ACCELERATED PUBLICATIONS
From the Guggenheim 1306, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905
Ataxia-telangiectasia-mutated and Rad3-related (ATR) plays an essential role in the maintenance of genome integrity and cell viability. The kinase is activated in response to DNA damage and initiates a checkpoint signaling cascade by phosphorylating a number of downstream substrates including Chk1. Unlike ataxia-telangiectasia-mutated (ATM), which appears to be mainly activated by DNA double-strand breaks, ATR can be activated by a variety of DNA damaging agents. However, it is still unclear what triggers ATR activation in response to such diverse DNA lesions. One model proposes that ATR can directly recognize DNA lesions, while other recent data suggest that ATR is activated by a common single-stranded DNA (ssDNA) intermediate generated during DNA repair. In this study, we show that UV lesions do not directly activate ATR in vivo. In addition, ssDNA lesions created during the repair of UV damage are also not sufficient to activate the ATR-dependent pathway. ATR activation is only observed in replicating cells indicating that replication stress is required to trigger the ATR-mediated checkpoint cascade in response to UV irradiation. Interestingly, H2AX appears to be required for the accumulation of ATR at stalled replication forks. Together our data suggest that ssDNA at arrested replication forks recruits ATR and initiates ATR-mediated phosphorylation of H2AX and Chk1. Phosphorylated H2AX might further facilitate ATR activation by stabilizing ATR at the sites of arrested replication forks.
Received for publication, December 22, 2003 , and in revised form, January 20, 2004.
* This work was supported by National Institutes of Health Grants CA89239 and CA92312 and the Breast Cancer Research Foundation. 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.
Supported by Postdoctoral Fellowship DAMD17-01-1-0317 from the Department of Defense (DOD) Breast Cancer Research program.
Recipient of a DOD breast cancer career development award. To whom correspondence should be addressed: Guggenheim 1306, Division of Oncology Research, Mayo Clinic, Guggenheim Bldg., Rm. 1342, 200 First St., SW, Rochester, MN 55905. Tel.: 507-538-1545; Fax: 507-284-3906; E-mail: Chen.junjie{at}mayo.edu.
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