ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
Although a small decrease in survival and increase in tumor incidence was observed in ATR(+/-) mice, ATR(-/-) embryos die early in development, subsequent to the blastocyst stage and prior to 7.5 days p.c. In culture, ATR(-/-) blastocysts cells continue to cycle into mitosis for 2 days but subsequently fail to expand and die of caspase-dependent apoptosis. Importantly, caspase-independent chromosome breaks are observed in ATR(-/-) cells prior to widespread apoptosis, implying that apoptosis is caused by a loss of genomic integrity. These data show that ATR is essential for early embryonic development and must function in processes other than regulation of p53.
Brown
E J
EJ
California Institute of Technology, Division of Biology, Pasadena, California 91125 USA.
Baltimore
D
D
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000502:physiology; D024682:BRCA2 Protein; D001755:Blastocyst / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D004260:DNA Repair / Q000235:genetics; D005313:Fetal Death / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D009363:Neoplasm Proteins / Q000502:physiology; D009374:Neoplasms, Experimental / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020169:Caspases