title: Loss of ATM kinase activity leads to embryonic lethality in mice.
abstract: Ataxia telangiectasia (A-T) mutated (ATM) is a key deoxyribonucleic acid (DNA) damage signaling kinase that regulates DNA repair, cell cycle checkpoints, and apoptosis. The majority of patients with A-T, a cancer-prone neurodegenerative disease, present with null mutations in Atm. To determine whether the functions of ATM are mediated solely by its kinase activity, we generated two mouse models containing single, catalytically inactivating point mutations in Atm. In this paper, we show that, in contrast to Atm-null mice, both D2899A and Q2740P mutations cause early embryonic lethality in mice, without displaying dominant-negative interfering activity. Using conditional deletion, we find that the D2899A mutation in adult mice behaves largely similar to Atm-null cells but shows greater deficiency in homologous recombination (HR) as measured by hypersensitivity to poly (adenosine diphosphate-ribose) polymerase inhibition and increased genomic instability. These results may explain why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. We propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with HR during embryogenesis.
authors.affiliation: Laboratory of Genome Integrity, Frederick Cancer Research and Development Center; National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA. jeremy.daniel@cpr.ku.dk
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Manuela
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Baeck-Seung
authors.initials: BS
authors.lastname: Lee
authors.forename: Zhi
authors.initials: Z
authors.lastname: Guo
authors.forename: Darius
authors.initials: D
authors.lastname: Filsuf
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Belkina
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: You
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Paull
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000201:enzymology; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D016678:Genome; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011995:Recombination, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D011065:Poly(ADP-ribose) Polymerases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases