Human immunodeficiency virus type 1 Vpr induces G2 checkpoint activation by interacting with the splicing factor SAP145

Yasuhiko Terada, Yuko Yasuda

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

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 γ-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 γ-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.

Original languageEnglish
Pages (from-to)8149-8158
Number of pages10
JournalMolecular and Cellular Biology
Volume26
Issue number21
DOIs
Publication statusPublished - 2006 Nov
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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