HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination.

Abstract

An ATM-dependent cellular signal, a DNA-damage response, has been shown to be involved during infection of human immunodeficiency virus type-1 (HIV-1), and a high incidence of malignant tumor development has been observed in HIV-1-positive patients. Vpr, an accessory gene product of HIV-1, delays the progression of the cell cycle at the G2/M phase, and ATR-Chk1-Wee-1, another DNA-damage signal, is a proposed cellular pathway responsible for the Vpr-induced cell cycle arrest. In this study, we present evidence that Vpr also activates ATM, and induces expression of gamma-H2AX and phosphorylation of Chk2. Strikingly, Vpr was found to stimulate the focus formation of Rad51 and BRCA1, which are involved in repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and biochemical analysis revealed that Vpr dissociates the interaction of p53 and Rad51 in the chromatin fraction, as observed under irradiation-induced DSBs. Vpr was consistently found to increase the rate of HR in the locus of I-SceI, a rare cutting-enzyme site that had been introduced into the genome. An increase of the HR rate enhanced by Vpr was attenuated by an ATM inhibitor, KU55933, suggesting that Vpr-induced DSBs activate ATM-dependent cellular signal that enhances the intracellular recombination potential. In context with a recent report that KU55933 attenuated the integration of HIV-1 into host genomes, we discuss the possible role of Vpr-induced DSBs in viral integration and also in HIV-1 associated malignancy.

• Authors: C Nakai-Murakami, M Shimura, M Kinomoto, Y Takizawa, K Tokunaga, T Taguchi, S Hoshino, K Miyagawa, T Sata, H Kurumizaka, A Yuo, Y Ishizaka
• Journal: Oncogene (Oncogene) Vol. 26 Issue 4 Pg. 477-86 (Jan 25 2007) ISSN: 0950-9232 [Print] England
• PMID: 16983346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• Gene Products, vpr
• Tumor Suppressor Proteins
• DNA
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases

Topics

• Ataxia Telangiectasia Mutated Proteins
• Cell Cycle Proteins (metabolism)
• Cells, Cultured
• DNA (metabolism)
• DNA Breaks, Double-Stranded
• DNA Repair
• DNA-Binding Proteins (metabolism)
• Gene Expression Regulation
• Gene Products, vpr (physiology)
• Humans
• Protein Serine-Threonine Kinases (metabolism)
• Recombination, Genetic
• Signal Transduction
• Tumor Suppressor Proteins (metabolism)