Hypersensitivity of<i>Ku80</i>-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, and development
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- 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
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- 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
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- 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
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- 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
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- 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
抄録
<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>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 94 (25), 13588-13593, 1997-12-09
Proceedings of the National Academy of Sciences
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詳細情報
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- CRID
- 1361699994986987776
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- NII論文ID
- 30016218764
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- ISSN
- 10916490
- 00278424
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- データソース種別
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