Enhancing survival of mouse oocytes following chemotherapy or aging by targeting bax and Rad51

Loro L. Kujjo, Tiina Laine, Ricardo J G Pereira, Wataru Kagawa, Hitoshi Kurumizaka, Shigeyuki Yokoyama, Gloria I. Perez

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    Abstract

    Background:Therapeutic approaches to preserve fertility in females undergoing cancer treatments are currently ineffective. This is partly due to limited knowledge of the molecular mechanisms that injured germ cells elicit to repair damage and survive or to abort repair and activate biochemical pathways leading to death. So far, we know that following spontaneously occurring or drug-induced DNA damage, the efficiency of DNA repair is a critical determinant of the cell's fate. The protein encoded by the Rad51 gene is one of several components recruited for homologous recombinationdependent DNA double-strand break repair in both somatic cells and germ cells. Recently, we showed that microinjection of recombinant Rad51 into AKR/J mouse oocytes decreased the extent of spontaneous DNA double-strand breaks, suppressed apoptosis, and restored the developmental competence in AKR/J embryos. Herein we characterized the nature of chemotherapy-induced lesions in oocytes, and the associated individual components of the DNA damage sensor and repair apparatus. For comparison, we also assessed parallel spontaneous changes in aging oocytes. Methods: Data collected were derived from: analysis of apoptosis; immunodepletion; oocyte microinjections; immunocytochemistry; immunofluorescence; and CHIP-like assays. Results:Our data show that: (i) DNA damage in oocytes can be induced by both chemotherapy and spontaneously by the aging process; (ii) oocytes possess the machinery and capability for repairing such DNA damage; (iii) Rad51 is a critical player in the repair of both chemotherapy-induced and spontaneously-sustained DNA damage; and (iv) in response to damage, oocytes exhibit an inverse functional relationship between presence of Bax and activity of Rad51. Conclusion/Significance: Our results establish Rad51 and/or Bax as potential candidates that can be targeted for development of individualized chemotherapeutic interventions that are effective, but minimal in toxicity. The use of Rad51 and Bax modulating compounds could offer women the opportunity to maintain fully functional germ cells despite cancer treatments or aging.

    Original languageEnglish
    Article numbere9204
    JournalPLoS One
    Volume5
    Issue number2
    DOIs
    Publication statusPublished - 2010 Feb 12

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    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    Kujjo, L. L., Laine, T., Pereira, R. J. G., Kagawa, W., Kurumizaka, H., Yokoyama, S., & Perez, G. I. (2010). Enhancing survival of mouse oocytes following chemotherapy or aging by targeting bax and Rad51. PLoS One, 5(2), [e9204]. https://doi.org/10.1371/journal.pone.0009204