Loss of ATM kinase activity leads to embryonic lethality in mice

J.A. Daniel; M. Pellegrini; D. Filsuf; A. Nussenzweig; N.V. Belkina; L. Feigenbaum; B.-S. Lee; B.P. Sleckman; Z. You; Zhiqun Guo; T.T. Paull

doi:10.1083/jcb.201204035

Loss of ATM kinase activity leads to embryonic lethality in mice

J.A. Daniel, M. Pellegrini, D. Filsuf, A. Nussenzweig, N.V. Belkina, L. Feigenbaum, B.-S. Lee, B.P. Sleckman, Z. You, Zhiqun Guo, T.T. Paull

Novo Nordisk Foundation Center for Protein Research

75 Citations (Scopus)

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 language	English
Journal	Journal of Cell Biology
Volume	198
Issue number	3
Pages (from-to)	295-304
Number of pages	10
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.201204035
Publication status	Published - 6 Aug 2012

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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.",

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AU - Daniel, J.A.

AU - Pellegrini, M.

AU - Filsuf, D.

AU - Nussenzweig, A.

AU - Belkina, N.V.

AU - Feigenbaum, L.

AU - Lee, B.-S.

AU - Sleckman, B.P.

AU - You, Z.

AU - Guo, Zhiqun

AU - Paull, T.T.

PY - 2012/8/6

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N2 - 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.

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Loss of ATM kinase activity leads to embryonic lethality in mice

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