Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells

Yasuhiro Murakawa, Eiichiro Sonoda, Louise J. Barber, Weihua Zeng, Kyoko Yokomori, Hiroshi Kimura, Atsuko Niimi, Alan Lehmann, Yu Zhao Guang, Helfrid Hochegger, Simon J. Boulton, Shunichi Takeda

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    Abstract

    Proteasome inhibitors are novel antitumor agents against multiple myeloma and other malignancies. Despite the increasing clinical application, the molecular basis of their antitumor effect has been poorly understood due to the involvement of the ubiquitin-proteasome pathway in multiple cellular metabolisms. Here, we show that treatment of cells with proteasome inhibitors has no significant effect on nonhomologous end joining but suppresses homologous recombination (HR), which plays a key role in DNA double-strand break (DSB) repair. In this study, we treat human cells with proteasome inhibitors and show that the inhibition of the proteasome reduces the efficiency of HR-dependent repair of an artificial HR substrate. We further show that inhibition of the proteasome interferes with the activation of Rad51, a key factor for HR, although it does not affect the activation of ATM, γH2AX, or Mre11. These data show that the proteasome-mediated destruction is required for the promotion of HR at an early step. We suggest that the defect in HR-mediated DNA repair caused by proteasome inhibitors contributes to antitumor effect, as HR plays an essential role in cellular proliferation. Moreover, because HR plays key roles in the repair of DSBs caused by chemotherapeutic agents such as cisplatin and by radiotherapy, proteasome inhibitors may enhance the efficacy of these treatments through the suppression of HR-mediated DNA repair pathways.

    Original languageEnglish (US)
    Pages (from-to)8536-8543
    Number of pages8
    JournalCancer research
    Volume67
    Issue number18
    DOIs
    StatePublished - Sep 15 2007

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Murakawa, Y., Sonoda, E., Barber, L. J., Zeng, W., Yokomori, K., Kimura, H., Niimi, A., Lehmann, A., Guang, Y. Z., Hochegger, H., Boulton, S. J., & Takeda, S. (2007). Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells. Cancer research, 67(18), 8536-8543. https://doi.org/10.1158/0008-5472.CAN-07-1166