CONSERVATION OF THE CHK1 CHECKPOINT PATHWAY IN MAMMALS - LINKAGE OF DNA-DAMAGE TO CDK REGULATION THROUGH CDC25

In response to DNA damage, mammalian cells prevent cell cycle progress ion through the control of critical cell cycle regulators. A human gen e was identified that encodes the protein Chk1, a homolog of the Schiz osaccharomyces pombe Chk1 protein kinase, which is required for the DN A damage checkpoint. Human Chk1 protein was modified in response to DN A damage. In vitro Chk1 bound to and phosphorylated the dual-specifici ty protein phosphatases Cdc25A, Cdc25B, and Cdc25C, which control cell cycle transitions by dephosphorylating cyclin-dependent kinases. Chk1 phosphorylates Cdc25C on serine-216. As shown in an accompanying pape r by Peng et al. in this issue, serine-216 phosphorylation creates a b inding site for 14-3-3 protein and inhibits function of the phosphatas e. These results suggest a model whereby in response to DNA damage, Ch k1 phosphorylates and inhibits Cdc25C, thus preventing activation of t he Cdc2-cyclin B complex and mitotic entry.