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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 γ-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.

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Acknowledgements

We are grateful to Dr T Takemori (National Institute of Infectious Diseases, Japan) to help for analysis by a Vantage flow cytometer. We also thank to Riken BRC for control adenovirus, AxCALac8, and HT1080 cells. Drs Slebos (National Institute of Environmental Health Science, USA), Jasin M (Memorial Sloan-Kettering Cancer Center, USA), Graham F (McMaster University, Canada), and Saito I (Institute of Medical Sciences, of Tokyo University, Japan) kindly provided us with pBHRF, pDR-GFP, adenovirus of I-SceI, and AxCALac8, respectively. We also thank to O'Connor M (KuDOS pharmaceuticals, England) for KU55933. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor and a Grant for research on Health Sciences focusing on Drug Innovation. Dr Nakai-Murakami is a research resident supported by the Japan Health Sciences Foundation.

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Correspondence to Y Ishizaka.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Nakai-Murakami, C., Shimura, M., Kinomoto, M. et al. HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination. Oncogene 26, 477–486 (2007). https://doi.org/10.1038/sj.onc.1209831

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Keywords

  • HIV-1
  • Vpr
  • DNA double-strand breaks
  • homologous recombination
  • Non-AIDS defining malignancies

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