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Updated: May 19, 2026
Whole-mount Imaging of Mouse Embryo Sensory Axon Projections
Published on: December 9, 2014
Loss of ATM kinase activity leads to embryonic lethality in mice
Jeremy A Daniel1, Manuela Pellegrini, Baeck-Seung Lee
1Laboratory 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
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.
Insights
Ataxia telangiectasia mutated (ATM) kinase activity is crucial for DNA repair and embryonic development. Kinase-inactive ATM mutations cause embryonic lethality and genomic instability, explaining their rarity in A-T patients.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Ataxia telangiectasia mutated (ATM) is a critical DNA damage signaling kinase.
- ATM regulates DNA repair, cell cycle checkpoints, and apoptosis.
- Most Ataxia telangiectasia (A-T) patients have null mutations in ATM.
Purpose of the Study:
- To investigate if ATM's functions depend solely on its kinase activity.
- To characterize mouse models with catalytically inactive ATM mutations.
Main Methods:
- Generated mouse models with single, catalytically inactivating point mutations in Atm (D2899A and Q2740P).
- Utilized conditional deletion to study the D2899A mutation in adult mice.
- Assessed homologous recombination (HR) deficiency via poly (ADP-ribose) polymerase (PARP) inhibition and genomic instability.
Main Results:
- Both D2899A and Q2740P mutations led to early embryonic lethality in mice.
- The D2899A mutation in adult mice mimicked Atm-null cells but showed a greater deficiency in homologous recombination (HR).
- Increased genomic instability and hypersensitivity to PARP inhibition were observed with the D2899A mutation.
Conclusions:
- ATM kinase activity is essential for embryogenesis and proper homologous recombination (HR) function.
- Kinase-inactive ATM mutations can interfere with HR during development.
- The findings may explain the rarity of kinase-inactive ATM missense mutations in classical A-T patients.
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