Human immunodeficiency virus type 1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear BRCA1 and gamma-H2AX focus formation.

Abstract

Eukaryotic cells have evolved a complex mechanism for sensing DNA damage during genome replication. Activation of this pathway prevents entry into mitosis to allow for either DNA repair or, in the event of irreparable damage, commitment to apoptosis. Under conditions of replication stress, the damage signal is initiated by the ataxia-telangiectasia-mutated and Rad3-related kinase ATR. We recently demonstrated that the human immunodeficiency virus type 1 (HIV-1) gene product viral protein R (Vpr) arrests infected cells in the G(2) phase via the activation of ATR. In the present study, we show that the activation of ATR by Vpr is analogous to activation by certain genotoxic agents, both mechanistically and in its downstream consequences. Specifically, we show a requirement for Rad17 and Hus1 to induce G(2) arrest as well as Vpr-induced phosphorylation of histone 2A variant X (H2AX) and formation of nuclear foci containing H2AX and breast cancer susceptibility protein 1. These results demonstrate that G(2) arrest mediated by the HIV-1 gene product Vpr utilizes the cellular signaling pathway whose physiological function is to recognize replication stress. These findings should contribute to a greater understanding of how HIV-1 manipulates the CD4(+)-lymphocyte cell cycle and apoptosis induction in the progressive CD4(+)-lymphocyte depletion characteristic of HIV-1 pathogenesis.

• Authors: Erik S Zimmerman, Junjie Chen, Joshua L Andersen, Orly Ardon, Jason L Dehart, Jana Blackett, Shailesh K Choudhary, David Camerini, Paul Nghiem, Vicente Planelles
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 24 Issue 21 Pg. 9286-94 (Nov 2004) ISSN: 0270-7306 [Print] United States
• PMID: 15485898 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BRCA1 Protein
• CD4 Antigens
• Cell Cycle Proteins
• DNA-Binding Proteins
• Gene Products, vpr
• H2AX protein, human
• Histones
• Schizosaccharomyces pombe Proteins
• Tumor Suppressor Proteins
• hus1 protein, S pombe
• vpr Gene Products, Human Immunodeficiency Virus
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• Atm protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Apoptosis
• Ataxia Telangiectasia Mutated Proteins
• BRCA1 Protein (genetics, metabolism)
• CD4 Antigens (metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Nucleus (genetics, metabolism)
• Cells, Cultured
• DNA-Binding Proteins
• G2 Phase
• Gene Expression Regulation
• Gene Products, vpr (genetics, metabolism)
• HIV-1 (physiology)
• Histones (genetics, metabolism)
• Humans
• Mice
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Interference
• Schizosaccharomyces pombe Proteins
• Thymus Gland (metabolism, pathology)
• Tumor Suppressor Proteins
• vpr Gene Products, Human Immunodeficiency Virus