Loss of ATM kinase activity leads to embryonic lethality in mice

Jeremy A. Daniel, Manuela Pellegrini, Baeck Seung Lee, Zhi Guo, Darius Filsuf, Natalya V. Belkina, Zhongsheng You, Tanya T. Paull, Barry P. Sleckman, Lionel Feigenbaum, André Nussenzweig

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69 Scopus citations

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.

Original languageEnglish
Pages (from-to)295-304
Number of pages10
JournalJournal of Cell Biology
Volume198
Issue number3
DOIs
StatePublished - Aug 2012

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    Daniel, J. A., Pellegrini, M., Lee, B. S., Guo, Z., Filsuf, D., Belkina, N. V., You, Z., Paull, T. T., Sleckman, B. P., Feigenbaum, L., & Nussenzweig, A. (2012). Loss of ATM kinase activity leads to embryonic lethality in mice. Journal of Cell Biology, 198(3), 295-304. https://doi.org/10.1083/jcb.201204035