DNA repair mechanisms / edited by Philip C. Hanawalt, Errol C. Friedberg, C. Fred Fox.

Date:
1978
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: DNA repair mechanisms / edited by Philip C. Hanawalt, Errol C. Friedberg, C. Fred Fox. Source: Wellcome Collection.

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    4 1. PETER A. CERUTTI DIRECT ACTION: attack of DNA by the primary agent or a chemical derivative of the primary agent. INDIRECT ACTION: (of ionizing radiation, ultraviolet radiation or a chemical) attack of DNA by active oxygen species which are formed by the reaction of the primary agent with a non-DNA target. In general, direct action is expected to predominate for most chemical damaging agents and for far-ultraviolet light while indirect action represents the major intracellular reaction mechanism for ionizing radiation. There is great variation in the structure of DNA lesions induced by direct chemical action. In contrast, a similar spectrum of lesions is expected to be introduced by indirect action of physical and chemical agents. They include: single- and double- strand breaks, products of the 5,6-dihydroxy-dihydrothymine type, damage at the thymine - methyl group, damage involving the other DNA bases, DNA-DNA, DNA-RNA and DNA-protein cross links. Evidence for indirect action of ultraviole_^ light and the chemical damaging agents ascorbic acid/Cu^ and benzo- (a)pyrene (B(a)P) in intact mammalian cells has recently been obtained in our laboratory. The formation of products of the 5,6-dihydroxy-dihydrothymine type (t^'^) and the abstraction of tritium from thymine-methyl [^H] was observed in HeLa cells upon irradiation with monochromatic light at 240, 260, 280, 313 and 365 nm. The efficiency of formation of t^'^ type products was comparable to thymine photodimer- ization in the near ultraviolet at 313nm(12)^ There is little doubt that these lesions are formed by indirect action of ultraviolet light. The formation of [Зн]Н„0 in baby hamster kidney cells (BHK) which had been prelabeled in their DNA with thymine-methyl[^H] was observed upon treatment with 2xlO~^M ascorbic acid/2xlO~^M Cu2+. It was estimated that after 4 hours of incubation approximately 0.2% of all thymine-methyl groups had reacted with hydroxyl-radicals yielding 5-Methylene-uracil radicals and water (M. Ide and P. Cerutti, unpublished). 5-methylene-uracil radicals may in part be repaired chemically to thirmine by hydrogen ab¬ straction from neighboring organic molecules and participate in secondary radical chain reactions which may result in DNA strand breakage and DNA cross-linking. BHK cells have retained the capacity in culture to metabolize B(a)P. Poly- cyclic aromatic hydrocarbons are in part metabolized by one- electron oxidation reactions. The 6-oxo-B(a)P-radical represents an important intermediate which is further oxidized to the stable metabolites 6,12-, 1, 6- and 3,6- B(a)p-dione. Lorentzen and Ts'o^^^ have speculated that the
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