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

    Research output: Contribution to journalArticle

    37 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

    Fingerprint

    Homologous Recombination
    HIV-1
    DNA Damage
    Genome
    Virus Integration
    Double-Stranded DNA Breaks
    G2 Phase
    Cell Cycle Checkpoints
    Cell Division
    Genetic Recombination
    Chromatin
    Neoplasms
    Cell Cycle
    Phosphorylation
    Incidence
    Enzymes
    Infection
    2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one

    Keywords

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

    ASJC Scopus subject areas

    • Molecular Biology
    • Cancer Research
    • Genetics

    Cite this

    Nakai-Murakami, C., Shimura, M., Kinomoto, M., Takizawa, Y., Tokunaga, K., Taguchi, T., ... 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

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

    In: Oncogene, Vol. 26, No. 4, 25.01.2007, p. 477-486.

    Research output: Contribution to journalArticle

    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, vol. 26, no. 4, pp. 477-486. https://doi.org/10.1038/sj.onc.1209831
    Nakai-Murakami C, Shimura M, Kinomoto M, Takizawa Y, Tokunaga K, Taguchi T et al. HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination. Oncogene. 2007 Jan 25;26(4):477-486. https://doi.org/10.1038/sj.onc.1209831
    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. / HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination. In: Oncogene. 2007 ; Vol. 26, No. 4. pp. 477-486.
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