Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

J Cell Biol. 2012 Aug 6;198(3):305-13. doi: 10.1083/jcb.201204098.


Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (Atm(KD/KD)) died during early embryonic development. Atm(KD/-) cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm(-/-) cells. Despite this increased genomic instability, Atm(KD/-) lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm(-/-) lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Catalysis
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / physiology*
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Exons
  • Female
  • Gene Expression Regulation, Developmental*
  • Gene Expression Regulation, Enzymologic*
  • Homozygote
  • Humans
  • Lymphocytes / cytology
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / physiology*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / physiology*


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases