ever, each oxidizing agent involved a significantly different set of genes, which also differed from those required for protection against X-rays, indicating that oxidative damage cannot be considered a single entity, but is dependent on the chemical source of the oxidation. Mutants sensitive to hydrogen peroxide included an overrepresentation of mitochondrial respiratory functions, but those sensitive to diamide encompassed genes involved in vacuolar protein sorting. This makes it especially difficult to predict what kinds of damage would result from endogenous reactive oxidative species. Endogenous damage could present its own unique spectrum of genes required for resistance, different from each of the exogenous sources as well as from ionizing radiation.

These results must be confirmed and extended to human cells, because the genes known to be involved in repair of DNA DSBs by NHEJ (Ku70, Ku80, and DNA-PK) were rarely found among those involved in resistance to ionizing radiation or oxidative damage in yeast, where they play a very minor role. The majority of genes required for resistance to oxidative damage were, however, considered by one set of authors (Thorpe and others 2004) as more representative of damage to the protein components of the cell than to DNA. These included genes required for transcription, protein trafficking, and vacuolar function.

These damage responses in S. cerevisiae are, however, dominated by the efficient homologous recombination that plays a major role in response to DNA damage (Kelley and others 2003). Homologous recombination may therefore mask some of the effects caused by loss of genes on pathways that may be minor in yeast but more important in mammalian cells (Swanson and others 1999; Gellon and others 2001; Morey and others 2003). For example, mice that are defective in apurinic endonuclease are embryonic lethals, and blastocysts derived from these nulls are radiosensitive (Xanthoudakis and others 1996; Ludwig and others 1998). RNAi ablation of a pyrimidine-specific DNA glycosylase in mice confers radiosensitivity (Rosenquist and others 2003). Although the results described in yeast do indicate differences between ionizing radiations and oxidizing agents, the extent of differences or of overlap may not be the same in mammalian cells.

These results in S. cerevisiae, however, provide no support for the attempts to equate low-dose ionizing radiation with endogenous oxidative reactions. The committee would expect even greater divergence between ionizing radiation and oxidative damage in human cells because of the higher ratio of cytoplasmic and nuclear proteins to DNA than in S. cerevisiae and the greater role of NHEJ.



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