Journal
JOURNAL OF CELL BIOLOGY
Volume 198, Issue 3, Pages 305-313Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201204098
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Funding
- St. Baldrick's Foundation
- Gabrielle Angel Foundation
- John Driscoll Jr. Children's Medical Award
- Leukemia Lymphoma Foundation
- graduate program of Pathobiology and Molecular Medicine at Columbia University
- National Institutes of Health/National Cancer Institute training grant [T32-CA09503]
- [CA158073]
- [CA148644]
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Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (Atm(KD/KD)) died during early embryonic development. Atm(KD/-) cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm(-/-) cells. Despite this increased genomic instability, Atm(KD/-) lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm(-/-) lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.
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