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J. Biol. Chem., Vol. 278, Issue 28, 25879-25886, July 11, 2003

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Activation of the ATR-mediated DNA Damage Response by the HIV-1 Viral Protein R^*

Mikhail Roshal  , Baek Kim , Yonghong Zhu ¶, Paul Nghiem || and Vicente Planelles ** 

From the Department of Microbiology and Immunology, University of Rochester Cancer Center, Rochester, New York 14642, ^¶DNAX Research, Inc., Palo Alto, California 94304, ^||Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, and ^**Division of Cellular Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132

DNA damage is a universal inducer of cell cycle arrest at the G₂ phase. Infection by the human immunodeficiency virus type 1 (HIV-1) also blocks cellular proliferation at the G₂ phase. The HIV-1 accessory gene vpr encodes a conserved 96-amino acid protein (Vpr) that is necessary and sufficient for the HIV-1-induced block of cellular proliferation. In the present study, we examined a recently identified DNA damage-signaling protein, the ATM- and Rad3-related protein, ATR, for its potential role in the induction of G₂ arrest by Vpr. We show that inhibition of ATR by pharmacological inhibitors, by expression of the dominant-negative form of ATR, or by RNA interference inhibits Vpr-induced cell cycle arrest. As with DNA damage, activation of ATR by Vpr results in phosphorylation of Chk1. This study provides conclusive evidence of activation of the ATR-initiated DNA damage-signaling pathway by a viral gene product. These observations are important toward understanding how HIV infection promotes cell cycle disruption, cell death, and ultimately, CD4+ lymphocyte depletion.

Received for publication, April 15, 2003 , and in revised form, May 6, 2003.

^* This work was supported in part by National Institutes of Health Research Grants R01AI49057 and R21AI054188 (to V. P.) and NR01AI49781 (to B. K.). 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 National Institutes of Health Grant T32AI49815.

To whom correspondence should be addressed: Dept. of Pathology, University of Utah School of Medicine, 30 N. 1900 East, SOM 5C210, Salt Lake City, UT 84132. Tel.: 801-581-8655; E-mail: vicente.planelles{at}path.utah.edu.

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