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.
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 G(2) 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 G(2) before decreasing to undetectable levels in mitotic and G(1) 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.
Mesh Terms:
Animals, Carrier Proteins, Cell Cycle, Cells, Cultured, Chromatin, Cullin Proteins, DNA Replication, DNA-Binding Proteins, Embryo, Mammalian, Female, HIV-1, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Binding, RNA Interference, Ubiquitin-Protein Ligases, vpr Gene Products, Human Immunodeficiency Virus
Animals, Carrier Proteins, Cell Cycle, Cells, Cultured, Chromatin, Cullin Proteins, DNA Replication, DNA-Binding Proteins, Embryo, Mammalian, Female, HIV-1, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Binding, RNA Interference, Ubiquitin-Protein Ligases, vpr Gene Products, Human Immunodeficiency Virus
Mol. Cell. Biol.
Date: Sep. 01, 2008
PubMed ID: 18606781
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