G2/M checkpoint control. DNA damage induces the ATM-mediated phosphorylation of chk2 as well as phosphorylation of chk1, both of which phosphorylate cdc25C, promoting its interaction with 14-3-3 proteins and its cytoplasmic sequestration. As a consequence, cdc25C cannot dephosphorylate cdc2, which remains in an inactive state, resulting in G2 arrest. p53 is also activated following DNA damage, inducing both 14-3-3ς and p21^Waf1/Cip1, both of which are important in the maintenance of cdc2 inhibition and G2 arrest. In cells lacking p53, disruption of cdc25C cytoplasmic sequestration facilitates mitotic entrance of damaged cells, resulting in cell death. Therefore, caffeine, which inhibits ATM-mediated kinase activity, and UCN-01, which targets chk1, limit phosphorylation of cdc25C, allowing activation of cdc2 and mitotic entry and selectively sensitizing p53-deficient cells to DNA-damaging agents. ATM contributes to p53 phosphorylation following DNA damage. This phosphorylation event is inhibited by high doses of caffeine, perhaps explaining why, at high caffeine concentration, some sensitization to DNA damage is also observed in cells expressing wild-type p53, although effects are still more pronounced in cells lacking p53. Low doses of caffeine specifically sensitize p53-deficient cells.