Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm.
Ataxia telangiectasia results from mutations of ATM and is characterized by severe neurodegeneration and defective responses to DNA damage. Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of endogenously formed DNA double-strand breaks during nervous system development. Here we report that Atm is required for apoptosis in all areas of the DNA ligase IV-deficient developing nervous system. However, Atm deficiency failed to rescue deficits in immune differentiation in DNA ligase IV-null mice. These data indicate that ATM responds to endogenous DNA lesions and functions during development to eliminate neural cells that have incurred genomic damage. Therefore, ATM could be important for preventing accumulation of DNA-damaged cells in the nervous system that might eventually lead to the neurodegeneration observed in ataxia telangiectasia.
Lee
Y
Y
Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Barnes
D E
DE
Lindahl
T
T
McKinnon
P J
PJ
D000818:Animals; D000831:Animals, Newborn; D034961:Antigens, Nuclear; D017209:Apoptosis / Q000502:physiology; D001260:Ataxia Telangiectasia; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000033:anatomy & histology / Q000254:growth & development; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D011088:DNA Ligases; D000072481:DNA Ligase ATP