Loss of ATM kinase activity leads to embryonic lethality in mice

Author:

Daniel Jeremy A.12,Pellegrini Manuela13,Lee Baeck-Seung4,Guo Zhi56,Filsuf Darius1,Belkina Natalya V.1,You Zhongsheng4,Paull Tanya T.5,Sleckman Barry P.4,Feigenbaum Lionel1,Nussenzweig André1

Affiliation:

1. Laboratory of Genome Integrity; Experimental Immunology Branch; and Science Applications International Corporation-Frederick, Frederick Cancer Research and Development Center; National Cancer Institute, National Institutes of Health, Bethesda, MD 20814

2. The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark

3. Department of Experimental Medicine, University of La Sapienza, 00184 Rome, Italy

4. Department of Pathology and Immunology and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110

5. Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78705

6. Department of Genetics, Harvard Medical School, Boston, MA 02115

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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