Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair |
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Authors: | Zhang Shichuan Yajima Hirohiko Huynh Hoangdinh Zheng Junke Callen Elsa Chen Hua-Tang Wong Nancy Bunting Samuel Lin Yu-Fen Li Mengxia Lee Kyung-Jone Story Michael Gapud Eric Sleckman Barry P Nussenzweig André Zhang Cheng Cheng Chen David J Chen Benjamin P C |
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Institution: | 1Division of Molecular Radiation Biology, Department of Radiation Oncology, and 2Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390;3Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 |
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Abstract: | The nonhomologous end-joining (NHEJ) pathway is essential for radioresistance and lymphocyte-specific V(D)J (variable diversity] joining) recombination. Defects in NHEJ also impair hematopoietic stem cell (HSC) activity with age but do not affect the initial establishment of HSC reserves. In this paper, we report that, in contrast to deoxyribonucleic acid (DNA)-dependent protein kinase catalytic subunit (DNA-PKcs)-null mice, knockin mice with the DNA-PKcs(3A/3A) allele, which codes for three alanine substitutions at the mouse Thr2605 phosphorylation cluster, die prematurely because of congenital bone marrow failure. Impaired proliferation of DNA-PKcs(3A/3A) HSCs is caused by excessive DNA damage and p53-dependent apoptosis. In addition, increased apoptosis in the intestinal crypt and epidermal hyperpigmentation indicate the presence of elevated genotoxic stress and p53 activation. Analysis of embryonic fibroblasts further reveals that DNA-PKcs(3A/3A) cells are hypersensitive to DNA cross-linking agents and are defective in both homologous recombination and the Fanconi anemia DNA damage response pathways. We conclude that phosphorylation of DNA-PKcs is essential for the normal activation of multiple DNA repair pathways, which in turn is critical for the maintenance of diverse populations of tissue stem cells in mice. |
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