Ionizing radiation causes both singly and multiply damaged sites in DNA when the range of radical migration is limited by the presence of hydroxyl radical scavengers (e.g. within cells). Multiply damaged sites are considered to be more biologically relevant because of the challenges they present to cellular repair mechanisms. These sites occur in the form of DNA double-strand breaks (dsb) but also as other multiple damages that can be converted to dsb during attempted repair. The presence of a dsb can lead to loss of base sequence information and/or can permit the two ends of a break to separate and rejoin with the wrong partner. (Multiply damaged sites may also be the biologically relevant type of damage caused by other agents, such as UVA, B and/or C light, and some antitumour antibiotics.) The quantitative data available from radiation studies of DNA are shown to support the proposed mechanisms for the production of complex damage in cellular DNA, i.e. via scavengable and non-scavengable mechanisms. The yields of complex damages can in turn be used to support the conclusion that cellular mutations are a consequence of the presence of these damages within a gene. Literature data are used to support these statements and to develop overall mechanisms connecting the production of primary species to the production of biologically relevant damages. The consequences of the LET of the radiation on multiplicity of damage are discussed and suggestions made for the cause of the decrease of the oxygen enhancement ratio as the LET increases.
The mechanisms of radiation damage production are used to examine the following premises: (1) the number of DNA double-strand breaks per unit dose increases with dose; (2) cell type to cell type variations in yield of DNA dsb per dose occur. Two stages of damage production are identified as possible sources of damage yield modulation; numbers of OH. free radicals reacting with the target, and amount of chemical repair occurring on the target radicals. These factors are discussed in the light of the structures within which cellular DNA is packaged and the known rate constants for the reactions involved. It is concluded from our current knowledge that, in the presence of oxygen: (a) the number of DNA dsb is linearly related to dose, and (b) the yields of DNA damage per dose among cell types are constant. There is a caveat to the latter conclusion: the chromatin structure may be different in radiosensitive cell lines. In the absence of such a difference, variations in radiosensitivity with dose or with cell type are assigned to differences in repair speed and/or accuracy.
Pulse-and steady-state radiolysis studies show two major differences in the radiation chemistry of aqueous solutions of E. coli DNA (DNA) and bromouracil substituted DNA (BU-DNA): on exposure of N 2 -saturated solutions to low doses of radiation the absorbance of BU-DNA increases while that of DNA decreases; the free radicals formed by OH attack on BU-DNA decay more rapidly than those on DNA. The differences are explained with the help of results from the accompanying paper by a mechanism involving conversion of the BU moiety of BU-DNA to a uracil (U) moiety by reaction of BU-DNA with organic free radicals. Uracil-5-yl radicals are formed which may abstract H from neighbouring deoxyribose moieties to give uracil and a radical which may lead to a single-strand break. A hypothesis for BU radiosensitization, based on these and earlier results, account for (a) more DNA base damage and (b) more single-strand breaks in BU-DNA than in DNA; and (c) formation of U in BU-DNA.' Current address:
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