Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

• DOI: 10.1083/jcb.201204098
• Publication Date: 2012-08-06T16:23:29Z
• Authors: Kenta Yamamoto; Yunyue Wang; Wenxia Jiang; Xiangyu Liu; Richard L. Dubois; Chyuan-Sheng Lin; Thomas Ludwig; Christopher J. Ba...; Shan Zha
• Keywords: 0301 basic medicine; Base Sequence; DNA Repair; Models, Genetic; Homozygote; Molecular Sequence Data; Gene Expression Regulation, Developmental; Cell Cycle Proteins; Mice, Transgenic; Ataxia Telangiectasia Mutated Proteins; Exons; Catalysis; Gene Expression Regulation, Enzymologic; DNA-Binding Proteins; Mice; 03 medical and health sciences; Animals; Humans; Female; Lymphocytes; Research Articles; Alleles; DNA Damage

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 (AtmKD/KD) died during early embryonic development. AtmKD/− cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm−/− cells. Despite this increased genomic instability, AtmKD/− 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.