AbstractBackgroundUpon exposure to agents that damage DNA,Saccharomyces cerevisiaeundergo widespread reprogramming of gene expression. Such a vast response may be due not only to damage to DNA but also damage to proteins, RNA, and lipids. Here the transcriptional response ofS. cerevisiaespecifically induced by DNA damage was discerned by exposingS. cerevisiaeto a panel of three "radiomimetic" enediyne antibiotics (calicheamicin γ1I, esperamicin A1 and neocarzinostatin) that bind specifically to DNA and generate varying proportions of single- and double-strand DNA breaks. The genome-wide responses were compared to those induced by the non-selective oxidant γ-radiation.ResultsGiven well-controlled exposures that resulted in similar and minimal cell death (~20–25%) across all conditions, the extent of gene expression modulation was markedly different depending on treatment with the enediynes or γ-radiation. Exposure to γ-radiation resulted in more extensive transcriptional changes classified both by the number of genes modulated and the magnitude of change. Common biological responses were identified between the enediynes and γ-radiation, with the induction of DNA repair and stress response genes, and the repression of ribosomal biogenesis genes. Despite these common responses, a fraction of the response induced by gamma radiation was repressed by the enediynes andvise versa, suggesting that the enediyne response is not entirely "radiomimetic." Regression analysis identified 55 transcripts with gene expression induction associated both with double- or single-strand break formation. TheS. cerevisiae"DNA damage signature" genes as defined by Gaschet al. [1] were enriched among regulated transcripts associated with single-strand breaks, while genes involved in cell cycle regulation were associated with double-strand breaks.ConclusionDissection of the transcriptional response in yeast that is specifically signaled by DNA strand breaks has identified that single-strand breaks provide the signal for activation of transcripts encoding proteins involved in the DNA damage signature inS. cerevisiae, and double-strand breaks signal changes in cell cycle regulation genes.