such damage. Modeling of electron interactions with DNA suggests that when more than one strand break occurs due to an electron interaction, approximately 30% of the breaks will be multiple events (three or more) that occur over a very small distance. These multiple events, sometimes referred to as LMDS, would be expected to occur at the same average rate per electron traversal of the DNA, whether the overall dose is high or low. It is reasonable to expect that multiple lesions of this sort would be more difficult to repair or might be prone to misrepair. This may explain the apparent inconsistency between the lethality and mutagenicity of agents that principally cause DNA single-strand breaks and ionizing radiation, which also produces double-strand breaks and LMDS. Furthermore, modeling of multiple damages in a small length of DNA suggests that the normal cellular oxidative damage of DNA may differ qualitatively from that due to ionizing radiation. Recent information is presented as an annex to this chapter, about a significant disparity in the genes that repair oxidative damage in yeast DNA and genes that repair radiation damage.
Approximately 4800 deletion mutations have been made in all the nonessential genes in the yeast Saccharomyces cerevisiae. These have been used by two groups of investigators to identify the genes responsible for resistance against ionizing radiation, ultraviolet light, cisplatin, and a number of different oxidizing agents (hydrogen peroxide, diamide, linoleic acid 13-hydroperoxide, menadione, and cumene hydroperoxide; Birrell and others 2001, 2002; Game and others 2003; Thorpe and others 2004; Wu and others 2004). The set of genes required for resistance against a particular agent is an indication of the nature of the cellular biochemical pathways required to restore viability and, indirectly, of the kind of damage generated by the agent. If a common set of genes is required for several different agents, these will point to a common or overlapping chemical nature of the damage. The striking observation about the results in S. cerevisiae is that the sets of genes required for resistance against each agent differed significantly from each other. When pairwise comparisons were made between ionizing radiation and each oxidant, the overlap was low: less than half of the genes required for resistance against ionizing radiation were also required for resistance to oxidative damage (Figures 1A-1, and 1A-2).
Large numbers of genes not obviously involved in DNA repair fall within the list of sensitive mutants to ionizing radiation and oxidants. Several genes whose deletion produced sensitivity to radiation and oxidants were involved in DNA replication and recombination, suggesting that this process was vulnerable to all kinds of cellular damage in yeast. In contrast, the most important genes in human cells for repair by NHEJ were not represented among the sensitive mutants because this is a minor pathway in yeast. An additional observation is that the set of genes whose expression was induced by damage differed from the genes required for resistance against each agent, implying that repair genes were not among those induced by damage (Birrell and others 2002).
The committee carried out a detailed comparison of the genes reported by each group, using publicly available data sets. One group (Birrell and others 2001, 2002; Game and others 2003) reported the response of the complete set of 4800 genes and ranked them in sequence, from most sensitive to least sensitive. About 10% of all genes (470) showed some degree of sensitivity to ionizing radiation. The other group (Thorpe and others 2004) reported only those genes that showed sensitivity to at least one oxidant (approximately 675 genes) and ranked them in categories 1–7, with the most sensitive in category 1.
Comparison between these data sets is complicated by different methods of reporting and different technical approaches to determining sensitivity. Comparisons were therefore made in general terms rather than gene by gene, and only those genes were considered that were reported by both groups. The committee first compared the genes required for resistance against hydrogen peroxide as reported by two independent research groups, to establish the consistency of the data (Figure 1A-1). A set containing about 200 genes was common to both groups as necessary for resistance to hydrogen peroxide. Of these, 150 were also sensitive to ionizing radiation. Since different methods were used to detect sensitivity and rank the strains, some differences are not surprising. The common set of 150 genes required for resistance to both ionizing radiation and hydrogen peroxide included those involved in postreplication repair and recombination, but the genes that ranked among the most sensitive toward ionizing radiation were ranked lower on the list for hydrogen peroxide (Birrell and others 2002).
The committee then compared the genes required for resistance to different oxidizing agents with those required for resistance to X-rays (Figure 1A-2). The overlap was small in comparison to the number of genes required for resistance to ionizing radiation; conversely, more than half of the genes required for resistance to each oxidant were also required for resistance to ionizing radiation. However, the same genes were not involved for each oxidant.
The implication of these results is that each agent that is toxic to S. cerevisiae produces a unique spectrum of cellular damage, with some overlap. The relevance of these comparisons to this report lies in the attempts that have been made to explain low-dose ionizing radiation as no more than a special case of oxidative damage (Pollycove and Feinendegen 2003). If this were true, low doses of ionizing radiation would be insignificant compared to the levels of naturally occurring reactive oxygen species and could therefore be ignored as having no detrimental health effects. How-