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Journal of Virology, December 2005, p. 15443-15451, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15443-15451.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of the ATR Pathway by Human Immunodeficiency Virus Type 1 Vpr Involves Its Direct Binding to Chromatin In Vivo

Maoyi Lai,1 Erik S. Zimmerman,2 Vicente Planelles,2 and Junjie Chen1*

Department of Molecular Pharmacology and Experimental Therapeutics, Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota,1 Division of Cellular Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah2

Received 20 April 2005/ Accepted 20 September 2005

The human immunodeficiency virus type 1 (HIV-1) protein Vpr (viral protein R) arrests cells in the G2 phase of the cell cycle, a process that requires activation of the ATR (ataxia-telangiectasia and Rad3-related) pathway. In this study we demonstrate that the expression of Vpr does not cause DNA double-strand breaks but rather induces ATR activation, as indicated by induction of Chk1 phosphorylation and the formation of {gamma}-H2AX and 53BP1 nuclear foci. We define a C-terminal domain containing repeated H(F/S)RIG sequences required for Vpr-induced activation of ATR. Further investigation of the mechanism by which Vpr activates the ATR pathway reveals an increase in chromatin binding of replication protein A (RPA) upon Vpr expression. Immunostaining shows that RPA localizes to nuclear foci in Vpr-expressing cells. Furthermore, we demonstrate direct binding of Vpr to chromatin in vivo, whereas Vpr C-terminal domain mutants lose this chromatin-binding activity. These data support a mechanism whereby HIV-1 Vpr induces ATR activation by targeting the host cell DNA and probably interfering with normal DNA replication.

* Corresponding author. Mailing address: Division of Oncology Research, Mayo Clinic, Guggenheim 1342, Rochester, MN 55905. Phone: (507) 538-1545. Fax: (507) 284-3906. E-mail: chen.junjie{at}mayo.edu.

Journal of Virology, December 2005, p. 15443-15451, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15443-15451.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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