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Molecular and Cellular Biology, November 2004, p. 9286-9294, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9286-9294.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Vpr-Mediated G₂ Arrest Requires Rad17 and Hus1 and Induces Nuclear BRCA1 and -H2AX Focus Formation

Division of Cellular Biology and Immunology, Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah,¹ Division of Oncology Research, Mayo Clinic, Rochester, Minnesota,² Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California,³ Cutaneous Biology Research Center, Harvard Medical School, Charlestown, Massachusetts⁴

Received 7 July 2004/ Returned for modification 29 July 2004/ Accepted 12 August 2004

Eukaryotic cells have evolved a complex mechanism for sensing DNA damage during genome replication. Activation of this pathway prevents entry into mitosis to allow for either DNA repair or, in the event of irreparable damage, commitment to apoptosis. Under conditions of replication stress, the damage signal is initiated by the ataxia-telangiectasia-mutated and Rad3-related kinase ATR. We recently demonstrated that the human immunodeficiency virus type 1 (HIV-1) gene product viral protein R (Vpr) arrests infected cells in the G₂ phase via the activation of ATR. In the present study, we show that the activation of ATR by Vpr is analogous to activation by certain genotoxic agents, both mechanistically and in its downstream consequences. Specifically, we show a requirement for Rad17 and Hus1 to induce G₂ arrest as well as Vpr-induced phosphorylation of histone 2A variant X (H2AX) and formation of nuclear foci containing H2AX and breast cancer susceptibility protein 1. These results demonstrate that G₂ arrest mediated by the HIV-1 gene product Vpr utilizes the cellular signaling pathway whose physiological function is to recognize replication stress. These findings should contribute to a greater understanding of how HIV-1 manipulates the CD4⁺-lymphocyte cell cycle and apoptosis induction in the progressive CD4⁺-lymphocyte depletion characteristic of HIV-1 pathogenesis.

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