Hypersensitivity of<i>Ku80</i>-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, and development

  • André Nussenzweig
    Departments of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Laboratory Animal Research Center, The Rockefeller University, New York, NY 10021
  • Karen Sokol
    Departments of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Laboratory Animal Research Center, The Rockefeller University, New York, NY 10021
  • Paul Burgman
    Departments of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Laboratory Animal Research Center, The Rockefeller University, New York, NY 10021
  • Ligeng Li
    Departments of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Laboratory Animal Research Center, The Rockefeller University, New York, NY 10021
  • Gloria C. Li
    Departments of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Laboratory Animal Research Center, The Rockefeller University, New York, NY 10021

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<jats:p>We recently have shown that mice deficient for the 86-kDa component (Ku80) of the DNA-dependent protein kinase exhibit growth retardation and a profound deficiency in V(D)J (variable, diversity, and joining) recombination. These defects may be related to abnormalities in DNA metabolism that arise from the inability of<jats:italic>Ku80</jats:italic>mutant cells to process DNA double-strand breaks. To further characterize the role of Ku80 in DNA double-strand break repair, we have generated embryonic stem cells and pre-B cells and examined their response to ionizing radiation.<jats:italic>Ku80</jats:italic><jats:sup>−/−</jats:sup>embryonic stem cells are more sensitive than controls to γ-irradiation, and pre-B cells derived from<jats:italic>Ku80</jats:italic>mutant mice display enhanced spontaneous and γ-ray-induced apoptosis. We then determined the effects of ionizing radiation on the survival, growth, and lymphocyte development in<jats:italic>Ku80</jats:italic>-deficient mice.<jats:italic>Ku80</jats:italic><jats:sup>−/−</jats:sup>mice display a hypersensitivity to γ-irradiation, characterized by loss of hair pigmentation, severe injury to the gastrointestinal tract, and enhanced mortality. Exposure of newborn<jats:italic>Ku80</jats:italic><jats:sup>−/−</jats:sup>mice to sublethal doses of ionizing radiation enhances their growth retardation and results in the induction of T cell-specific differentiation. However, unlike severe combined immunodeficient mice, radiation-induced T cell development in<jats:italic>Ku80</jats:italic><jats:sup>−/−</jats:sup>mice is not accompanied by extensive thymocyte proliferation. The response of<jats:italic>Ku80</jats:italic>-deficient cell lines and mice to DNA-damaging agents provides important insights into the role of Ku80 in growth regulation, lymphocyte development, and DNA repair.</jats:p>

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