Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair

Shichuan Zhang, Hirohiko Yajima, HoangDinh Huynh, Junke Zheng, Elsa Callen, Hua Tang Chen, Nancy Wong, Samuel Bunting, Yu Fen Lin, Mengxia Li, Kyung-Jong Lee, Michael D Story, Eric Gapud, Barry P. Sleckman, André Nussenzweig, Chengcheng Zhang, David J Chen, Ping-chi B Chen

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

The nonhomologous end-joining (NHEJ) pathway is essential for radioresistance and lymphocytespecific 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-PKcs3A/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 DNAPKcs3A/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-PKcs3A/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.

Original languageEnglish (US)
Pages (from-to)295-305
Number of pages11
JournalJournal of Cell Biology
Volume193
Issue number2
DOIs
StatePublished - Apr 18 2011

ASJC Scopus subject areas

  • Cell Biology

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    Zhang, S., Yajima, H., Huynh, H., Zheng, J., Callen, E., Chen, H. T., Wong, N., Bunting, S., Lin, Y. F., Li, M., Lee, K-J., Story, M. D., Gapud, E., Sleckman, B. P., Nussenzweig, A., Zhang, C., Chen, D. J., & Chen, P. B. (2011). Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. Journal of Cell Biology, 193(2), 295-305. https://doi.org/10.1083/jcb.201009074