Transcriptional response of Saccharomyces cerevisiae to DNA-damaging agents does not identify the genes that protect against these agents

Abstract

The recent completion of the deletion of all of the nonessential genes in budding yeast has provided a powerful new way of determining those genes that affect the sensitivity of this organism to cytotoxic agents. We have used this system to test the hypothesis that genes whose transcription is increased after DNA damage are important for the survival to that damage. We used a pool of 4,627 diploid strains each with homozygous deletion of a nonessential gene to identify those genes that are important for the survival of yeast to four DNA-damaging agents: ionizing radiation, UV radiation, and exposure to cisplatin or to hydrogen peroxide. In addition we measured the transcriptional response of the wild-type parental strain to the same DNA-damaging agents. We found no relationship between the genes necessary for survival to the DNA-damaging agents and those genes whose transcription is increased after exposure. These data show that few, if any, of the genes involved in repairing the DNA lesions produced in this study, including double-strand breaks, pyrimidine dimers, single-strand breaks, base damage, and DNA cross-links, are induced in response to toxic doses of the agents that produce these lesions. This finding suggests that the enzymes necessary for the repair of these lesions are at sufficient levels within the cell. The data also suggest that the nature of the lesions produced by DNA-damaging agents cannot easily be deduced from gene expression profiling.

Figure 1

The relationship between gene expression and sensitivity to the four DNA-damaging agents. In each panel the 100 most sensitive strains with homozygous deletion of different genes are ranked from 1 to 100 from most to least sensitive strains. For each gene in these 100 most sensitive deletion strains the ratio of gene expression compared with controls is averaged for the first three time points after exposure of the wild-type strain to the DNA-damaging agent. The y axis is plotted as log₂ of gene expression ratio, which gives equal distance to a doubling and halving of the gene expression in the treated compared with control samples. Each gene is shown ± 1 standard error of the expression ratio based upon the three different time points for that gene.