Caffeine inhibits the checkpoint kinase ATM

The basis of many anti-cancer therapies is the use of genotoxic agents that damage DNA and thus kill dividing cells. Agents that cause cells to overri de the DNA damage checkpoint are predicted to sensitize cells to killing by genotoxic agents. They have therefore been sought as adjuncts in radiation therapy and chemotherapy. One such compound, caffeine, uncouples cell-cycl e progression from the replication and repair of DNA [1,2]. Caffeine theref ore serves as a model compound in establishing the principle that agents th at override DNA-damage checkpoints can be used to sensitize cells to the ki lling effects of genotoxic drugs [3]. But despite more than 20 years of use , the molecular mechanisms by which caffeine affects the cell cycle and che ckpoint responses have not been identified. We investigated the effects of caffeine on the G2/M DNA-damage checkpoint in human cells. We report that t he radiation induced activation of the kinase Cds1 [4] (also known as Chk2 [5]) is inhibited by caffeine in vivo and that ATM kinase activity is direc tly inhibited by caffeine in vitro. Inhibition of ATM provides a molecular explanation of the attenuation of DNA-damage checkpoint responses and for t he increased radiosensitivity of caffeine-treated cells [6-8].