Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice

The recent discovery of checkpoint kinases has suggested the conservation o f checkpoint mechanisms between yeast and mammals. In yeast, the protein ki nase Chk1 is thought to mediate signaling associated with the DNA damage ch eckpoint of the cell cycle. However, the function of Chk1 in mammals has re mained unknown. Targeted disruption of Chk1 in mice showed that Chk1(-/-) e mbryos exhibit gross morphologic abnormalities in nuclei as early as the bl astocyst stage. In culture, Chk1(-/-) blastocysts showed a severe defect in outgrowth of the inner cell mass and died of apoptosis. DNA replication bl ock and DNA damage failed to arrest the cell cycle before initiation of mit osis in Chk1(-/-) embryos. These results may indicate that Chk1 is indispen sable for cell proliferation and survival through maintaining the G(2) chec kpoint in mammals.