Incubation of mouse L cells in the presence of 2 mM caffeine immediately after ultraviolet irradiation causes a decrease in their colony-forming ability, compared to cells incubated in the absence of caffeine. To better understand this phenomenon, a study has been made of the effect of caffeine on cell progression and DNA synthesis in unirradiated cells and UV-irradiated cells. Unirradiated cells grow and proliferate in the presence of 2 mM caffeine, though it does cause small delays in the progression of G1 cells to S phase and G2 cells to mitosis and increase the doubling time of such cells from 16 hours to 18 to 20 hours. After low exposures of UV irradiation ($100\ {\rm ergs}/{\rm mm}^{2}$ or less), caffeine causes a specific block in the progression of UV-irradiated cells through S phase. Caffeine does not cause any additional delay in the progression of cells irradiated in G1 phase to S phase or in cells irradiated in G2 phase to mitosis. The number of cells stopped in S phase by the presence of caffeine can be quantitatively correlated with the loss of cell colony-forming ability. These studies indicate that caffeine acts specifically in S phase. Possible models for its mode of action are discussed.

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