Effects of caffeine and theophylline on dna synthesis in unirradiated and UV-irradiated mammalian cells

Abstract

Summary The effects of caffeine and theophylline on the rate of DNA synthesis and on the size of newly synthesized DNA made in unirradiated and UV-irradiated rodent cell lines have been examined. The principal and most dramatic effect exerted by these methylsted xanthines was an inhibition, at relatively low doses of the drugs (0.8-1.5 m M ), of a “post-replication repair” process in UV-irradiated cells. Gaps left in daughter DNA strands opposite UV-induced pyrimidine dimers in the parental strands, are normally sealed within a few hours after their formation. In the presence of caffeine or theophylline, this gap-filling process was specifically and strongly inhibited. As a consequence, in UV-irradiated cells low molecular weight pieces 0 newly syn- thesized DNA accumulated in the presence of caffeine or theophylline, whereas in their absence, the new DNA eventually attained the size of that in unirradiated cells. In unirradiated cells, caffeine and theophylline exerted smaller effects, and higher doses (1.5 m M or more) hacl to be used. At these high doses, DNA synthesis was inhibited and the newly synthesizecl DNA was made in smaller units than in untreated cells. Both the integrity and the repair of pre-existing DNA were unaffected by caffeine, These results may account for the well-documented sensitization of cells to UV light by caffeine and theophylline, and for the observations that caffeine exerts many of its cytological effects in cultured mammalian cells only if it is present during the DNA synthesis period.