Mechanisms of Radiation-Induced Mutagenesis in Mammalian Cells

摘要

Irradiation of DNA produces numerous different types of damage, differing according to which DNA component is modified (base, sugar) and the extent of the damage within a given segment of DNA. Attempts have been made to quantify simple forms of damage in cellular DNA, although as yet these have yielded reliable values for only a few damage types. For example, the use of enzymes or antibodies recognising specific forms of base damage has recently allowed relatively accurate measurements of both steady-state levels of damage and the radiation yield. Thus a major form of oxidative damage to guanine, 8-hydroxyguanine, has been found at steady state levels of 500-2000 per cell (depending on cell type), and the level induced in cellular DNA by γ rays is about 250/cell Gy~(-1). It is much more difficult to obtain steady-state measurements of more complex forms of damage, although radiation-induced levels of such damage as DNA DSBs have been measured in relatively small genomes (such as yeast) with some accuracy after high doses. Knowledge of radiation track structure has also been used to predict the frequencies of different damage types, including more complex forms (e.g. DSBs), or a DSB with adjacent damage. Again these techniques still require considerable refinement, although it is possible to make some general statements; e.g., that the occurrence of more complex types of damage will increase with increasing density of ionisation. While some of the forms of damage caused by radiation may also occur endogenously, as a by-product of cellular metabolism (e.g. oxidative radicals), the more complex forms of radiation-induced damage may be unique, since localised concentrations of endogenous radicals are less likely to occur in the immediate vicinity of DNA.