| Research Abstract |
The transmission of genetic information relies on checkpoint responses to errors affecting the integrity, replication, and segregation of the genome. A defect in checkpoint mechanisms can result in genetic instability and lead to the transformation of normal cells into cancer cells. Many genes that contribute to checkpoint mechanisms were initially identified in fission or budding yeast as a result of mutations that disrupt cell cycle checkpoints, and the recent discovery of their mammalian counterparts has suggested the conservation of checkpoint mechanisms between yeast and mammals. In fission yeast, the protein kinases Chk1 and Cds1 cooperatively function in cell cycle arrest upon DNA damage through regulating Cdc25. However, the functions of these kinases in mammals have remained unknown. Targeted disruption of Chk1 and Cds1 genes in mice revealed that Chk1-/- mice exhibited early embryonic lethality before E7.5 and its embryos exhibit gross morphologic abnormalities in nuclei as early as the blastocyst stage. DNA replication block and DNA damage failed to arrest the cell cycle before initiation of mitosis in Chk1-/- embryos. Thus, Chk1 is indispensable for cell proliferation and survival through maintaining the G2/M checkpoints in mammals. In contrast, Cds1-/- mice were viable and fertile, and its MEFs did not show the remarkable defects in G2/M checkpoints. Alternatively, Cds1-/- thymocytes were resistant to IR-induced and p53-dependent apoptosis. Taken together, these results clearly suggest that, in mammals, Chk1 and Cds1 kinases play important roles in distinct signal pathways upon DNA damage through regulating Cdc25 and p53, respectively.
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