ATR disruption leads to chromosomal fragmentation and early embryonic lethality

Genes Dev. 2000 Feb 15;14(4):397-402.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Ataxia Telangiectasia Mutated Proteins
  • BRCA1 Protein / physiology
  • BRCA2 Protein
  • Blastocyst / pathology
  • Caspases / metabolism
  • Cell Cycle Proteins*
  • Cell Transformation, Neoplastic / genetics
  • Chromosome Aberrations*
  • DNA Repair / genetics
  • Fetal Death / genetics*
  • Gene Expression Regulation, Developmental*
  • Gene Targeting
  • Genotype
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitosis
  • Neoplasm Proteins / physiology
  • Neoplasms, Experimental / genetics
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Transcription Factors / physiology

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Transcription Factors
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • Caspases