Mechanisms of Resistance to Ionising Radiations: Genetic and Molecular Studies on Ataxia-Telangiectasia and Related Radiation-Sensitive Mutants

Abstract

In mammalian cells the mechanisms of resistance to damage caused by ionising radiations (IR) are largely unknown. Knowledge of the types of damage induced and of the enzymes, identified mostly in lower organisms, which act upon that damage may suggest that certain mechanisms are likely to prevail. However, in this respect, the diversity of damage caused by IR in the genetic material (and presumably in some other cellular molecules) leads to some uncertainty; a large number of different types of altered chemical products have been identified in irradiated DNA (Hutchinson, 1985; Teoule, 1987). This suggests that a large number of enzymes may be involved in recovery from IR damage, although some will be more important than others when considering a given cellular response. IR-induced cell killing, for example, has been linked to the production of DNA strand breakage, especially double-strand breaks (dsb). In E. coli there are a number of genes affecting in the repair of dsb; mutations in these genes lead to a reduction in the efficiency of dsb rejoining to varying extents and to enhanced sensitivity to IR (e.g., Sargentini and Smith 1986). Probably the best example to illustrate this link is the use of an X-ray-sensitive yeast mutant rad54-3 which is also temperature-sensitive: it can repair dsb at 23¼ but not at 36°C and shows a quantitative recovery of radiation resistance as the temperature is shifted to allow dsb repair (Frankenberg-Schwager, et al., 1988). Additionally, in yeast it has been found that the induction of approximately one dsb by IR is equivalent to one lethal event in the absence of repair (Ho, 1975; Resnick and Martin, 1976; Frankenberg, et al., 1981). These analyses show that mutants sensitive to IR are potentially useful in defining mechanisms, although such mutants have to be carefully characterized before they can be of value.