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- W4256292725 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. PMID: 21482716 Funding information This work was supported by: NCI NIH HHS, United States Grant ID: R01 CA050519 NCI NIH HHS, United States Grant ID: CA50519 NCI NIH HHS, United States Grant ID: K01 CA120099 NCI NIH HHS, United States Grant ID: R37 CA050519 NCI NIH HHS, United States Grant ID: CA120099" @default.
- W4256292725 created "2022-05-12" @default.
- W4256292725 creator A5029892501 @default.
- W4256292725 date "2011-05-03" @default.
- W4256292725 modified "2023-10-05" @default.
- W4256292725 title "Faculty Opinions recommendation of Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair." @default.
- W4256292725 doi "https://doi.org/10.3410/f.10199956.10991054" @default.
- W4256292725 hasPublicationYear "2011" @default.
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