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Molecular and Cellular Biology, September 2008, p. 5621-5633, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00232-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Vpr-Binding Protein VprBP, a WD40 Protein Associated with the DDB1-CUL4 E3 Ubiquitin Ligase, Is Essential for DNA Replication and Embryonic Development

Chad M. McCall,^1,2, Paula L. Miliani de Marval,^1,2, Paul D. Chastain II,³ Sarah C. Jackson,^1,2 Yizhou J. He,^1,2 Yojiro Kotake,^1,2 Jeanette Gowen Cook,^1,2 and Yue Xiong^1,2,4*

Department of Biochemistry and Biophysics,¹ Lineberger Comprehensive Cancer Center,² Department of Pathology and Laboratory Medicine,³ Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599⁴

Received 12 February 2008/ Returned for modification 3 March 2008/ Accepted 9 June 2008

Damaged DNA binding protein 1, DDB1, bridges an estimated 90 or more WD40 repeats (DDB1-binding WD40, or DWD proteins) to the CUL4-ROC1 catalytic core to constitute a potentially large number of E3 ligase complexes. Among these DWD proteins is the human immunodeficiency virus type 1 (HIV-1) Vpr-binding protein VprBP, whose cellular function has yet to be characterized but has recently been found to mediate Vpr-induced G₂ cell cycle arrest. We demonstrate here that VprBP binds stoichiometrically with DDB1 through its WD40 domain and through DDB1 to CUL4A, subunits of the COP9/signalsome, and DDA1. The steady-state level of VprBP remains constant during interphase and decreases during mitosis. VprBP binds to chromatin in a DDB1-independent and cell cycle-dependent manner, increasing from early S through G₂ before decreasing to undetectable levels in mitotic and G₁ cells. Silencing VprBP reduced the rate of DNA replication, blocked cells from progressing through the S phase, and inhibited proliferation. VprBP ablation in mice results in early embryonic lethality. Conditional deletion of the VprBP gene in mouse embryonic fibroblasts results in severely defective progression through S phase and subsequent apoptosis. Our studies identify a previously unknown function of VprBP in S-phase progression and suggest the possibility that HIV-1 Vpr may divert an ongoing chromosomal replication activity to facilitate viral replication.

Published ahead of print on 7 July 2008.

These authors contributed equally to this work.

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