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

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

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    39 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)477-486
    Number of pages10
    JournalOncogene
    Volume26
    Issue number4
    DOIs
    Publication statusPublished - 2007 Jan 25

    Keywords

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

    ASJC Scopus subject areas

    • Molecular Biology
    • Cancer Research
    • Genetics

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  • Cite this

    Nakai-Murakami, C., Shimura, M., Kinomoto, M., Takizawa, Y., Tokunaga, K., Taguchi, T., Hoshino, S., Miyagawa, K., Sata, T., Kurumizaka, H., Yuo, A., & Ishizaka, Y. (2007). HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination. Oncogene, 26(4), 477-486. https://doi.org/10.1038/sj.onc.1209831