This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: MCB.01170-06v1 26/21/8149    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Terada, Y. Articles by Yasuda, Y. Search for Related Content PubMed PubMed Citation Articles by Terada, Y. Articles by Yasuda, Y.

Human Immunodeficiency Virus Type 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 55455,¹ Louis Pasteur Center for Medical Research, Cell Biology Section, Division of Basic Research, 103-5, Tanaka Monzen-cho, Sakyo-ku, Kyoto 606-8225, Japan²

Received 28 June 2006/ Returned for modification 4 August 2006/ Accepted 8 August 2006

Vpr, the viral protein R of human immunodeficiency virus type 1, induces G₂ cell cycle arrest and apoptosis in mammalian cells via ATR (for "ataxia-telangiectasia-mediated and Rad3-related") checkpoint activation. The expression of Vpr induces the formation of the -histone 2A variant X (H2AX) and breast cancer susceptibility protein 1 (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 colocalizes 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 the 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 the 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.

Supplemental material for this article may be found at http://mcb.asm.org/.

Published ahead of print on 21 August 2006.

This article has been cited by other articles:

• Poon, B., Chang, M. A., Chen, I. S. Y. (2007). Vpr Is Required for Efficient Nef Expression from Unintegrated Human Immunodeficiency Virus Type 1 DNA. J. Virol. 81: 10515-10523 [Abstract] [Full Text]