Activation of the ATR pathway by human immunodeficiency virus type 1 Vpr involves its direct binding to chromatin in vivo

作者：Lai MY; Zimmerman ES; Planelles V; Chen JJ^*

来源：Journal of Virology, 2005, 79(24): 15443-15451.

DOI：10.1128/JVI.79.24.15443-15451.2005

The human immunodeficiency virus type 1 (HIV-1) protein Vpr (viral protein R) arrests cells in the G(2) phase of the cell cycle, a process that requires activation of the ATR (ataxia- telangiectas ia and Rad3-related) pathway. In this study we demonstrate that the expression of Vpr does not cause DNA double-strand breaks but rather induces ATR activation, as indicated by induction of Chk1 phosphorylation and the formation of -gamma-H2AX and 53BP1 nuclear foci. We define a C-terminal domain containing repeated H(F/S)RIG sequences required for Vpr-induced activation of ATR. Further investigation of the mechanism by which Vpr activates the ATR pathway reveals an increase in chromatin binding of replication protein A (RPA) upon Vpr expression. Immunostaining shows that RPA localizes to nuclear foci in Vpr-expressing cells. Furthermore, we demonstrate direct binding of Vpr to chromatin in vivo, whereas Vpr C-terminal domain mutants lose this chromatin-binding activity. These data support a mechanism whereby HIV-1 Vpr induces ATR activation by targeting the host cell DNA and probably interfering with normal DNA replication.

• 出版日期2005-12