ATR disruption leads to chromosomal fragmentation and early embryonic lethality

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 inATR ^−/− 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.