title: Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice.
abstract: 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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yunyue
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenxia
authors.initials: W
authors.lastname: Jiang
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dubois
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bakkenist
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases