Rapid destruction of human Cdc25A in response to DNA damage

To protect genome integrity and ensure survival, eukaryotic cells exposed t o genotoxic stress cease proliferating to provide time for DNA repair. Huma n cells responded to ultraviolet light or ionizing radiation by rapid, ubiq uitin- and proteasome-dependent protein degradation of Cdc25A, a phosphatas e that is required for progression from G(1) to S phase of the cell cycle. This response involved activated Chk1 protein kinase but not the p53 pathwa y, and the persisting inhibitory tyrosine phosphorylation of Cdk2 blocked e ntry into S phase and DNA replication. Overexpression of Cdc25A bypassed th is mechanism, leading to enhanced DNA damage and decreased cell survival. T hese results identify specific degradation of Cdc25A as part of the DNA dam age checkpoint mechanism and suggest how Cdc25A overexpression in human can cers might contribute to tumorigenesis.