EFFECTS OF A NOVEL DNA-DAMAGING AGENT ON THE BUDDING YEAST SACCHAROMYCES-CEREVISIAE CELL-CYCLE

We have investigated the effects on Saccharomyces cerevisiae of a nove l antitumour agent (FCE24517 or Tallimustine) which causes selective a lkylations to adenines in the minor groove of DNA. Tallimustine, added to wild-type cells for short periods, reduced the growth rate and inc reased the percentage of budded cells and delayed the cell cycle in th e late S+G(2)+M phases. In the rad9 Delta null mutant cells, Tallimust ine treatment did not affect growth rate and the percentage of budded cells but greatly reduced cell viability compared to isogenic cells. C onsistent with a role of RAD9 in inducing a transient delay in G(2) ph ase which preserves cell viability, the potent cytotoxic effect of the drug on lad9 Delta cells was alleviated by treatment with nocodazole. Tallimustine was also found to delay the resumption from G, arrest of wild-type but not of lad9 Delta cells. These data indicate that the e ffects of Tallimustine on cell cycle progression in yeast are mediated by the RAD9 gene product. From our data it appears that yeast could b e a valuable model system to study the mode of action of this alkylati ng drug and of minor groove alkylators in general.