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

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 developm...

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Bibliographic Details
Published in:The Journal of cell biology 2012-08, Vol.198 (3), p.305-313
Main Authors: Yamamoto, Kenta, Wang, Yunyue, Jiang, Wenxia, Liu, Xiangyu, Dubois, Richard L, Lin, Chyuan-Sheng, Ludwig, Thomas, Bakkenist, Christopher J, Zha, Shan
Format: Article
Language:English
Subjects:
Alleles
Animals
Ataxia Telangiectasia Mutated Proteins
Base Sequence
Catalysis
Cell Cycle Proteins - genetics
Cell Cycle Proteins - physiology
Cellular biology
DNA Damage
DNA Repair
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Exons
Female
Gene Expression Regulation, Developmental
Gene Expression Regulation, Enzymologic
Homozygote
Humans
Kinases
Lymphocytes - cytology
Mice
Mice, Transgenic
Models, Genetic
Molecular Sequence Data
Mutation
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - physiology
Proteins
Rodents
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - physiology
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201204098