Y. Sanchez et al., CONSERVATION OF THE CHK1 CHECKPOINT PATHWAY IN MAMMALS - LINKAGE OF DNA-DAMAGE TO CDK REGULATION THROUGH CDC25, Science, 277(5331), 1997, pp. 1497-1501
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.