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Mol. Cell. Biol. doi:10.1128/MCB.01170-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

HIV-1 Vpr induces G2 checkpoint activation by interacting with the splicing factor SAP145

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis Minnesota, 55455; Louis Pasteur Center for Medical Research, Cell Biology Section, Division of Basic Research, 103-5, Tanaka Monzen-cho, Sakyo-ku, Kyoto 606-8225, Japan

^* To whom correspondence should be addressed. Email: terad002{at}umn.edu,

	Abstract

Vpr, the viral protein R of the Human Immunodeficiency Virus type 1 (HIV-1) induces G2 cell cycle arrest and apoptosis in mammalian cells via ATR (ataxia-telangiectasia-mediated and Rad3-related) checkpoint activation. Expression of Vpr induces the formation of the -H2AX and BRCA1 nuclear foci, and a C-terminal domain is required for Vpr-induced ATR activation and its nuclear localization. However, the cellular target of Vpr as well as the mechanism of G2 checkpoint activation was unknown. Here we report that Vpr induces checkpoint activation and G2 arrest by binding to the CUS1 domain of SAP145 and interfering with the functions of the SAP145 and SAP49 proteins, two subunits of the multimeric splicing factor 3b (SF3b). Vpr interacts with and co-localizes with SAP145 through its C-terminal domain in a speckled distribution. The depletion of either SAP145 or SAP49 leads to checkpoint-mediated G2 cell cycle arrest through induction of nuclear foci containing -H2AX and BRCA1. In addition, the expression of Vpr excludes SAP49 from the nuclear speckles and inhibits the formation of SAP145-SAP49 complex. To conclude these results point out the unexpected roles of the SAP145-SAP49 splicing factors in cell cycle progression, and suggest that cellular expression of Vpr induces checkpoint activation and G2 arrest by interfering with the function of SAP145-SAP49 complex in host cells.

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