DNA Damage Dictates the Biological Consequences of Ionizing Irradiation

Bernhard, William A.; Close, David M.

doi:10.1201/9780203913284.ch15

Cited by 43 publications

(84 citation statements)

References 158 publications

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“…The deoxyribose radical formed by hydrogen atom loss at the C1′ position (C1′•) is known to result in an alkali labile strand break, whereas the C3′•, C4′• and C5′• sugar radicals can lead to frank strand breaks (5–7). Although some progress has been made in understanding the sugar radicals that are present in DNA irradiated at low temperatures, using both low and high LET radiation (8–13), there is, as yet, no clear picture of the radiation yield of the individual sugar radicals formed and stabilized at low temperatures in irradiated DNA. Thus, there is a substantial ongoing effort to identify and characterize the radicals formed on the deoxyribose-phosphate backbone in irradiated DNA and on the sugar moiety in DNA nucleoside/tide model compounds (8–15).…”

Section: Introductionmentioning

confidence: 99%

“…Two mechanisms for sugar radical formation have been recently described. In one, photo-excitation of a base radical cation results in charge and unpaired spin transfer to the sugar followed by deprotonation from the sugar (12,13); a second invokes low energy electron induced C–O or P–O bond dissociation resulting in radicals from phosphate loss (16,17). …”

Section: Introductionmentioning

confidence: 99%

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UVA-visible photo-excitation of guanine radical cations produces sugar radicals in DNA and model structures

Adhikary

Malkhasian

Collins

et al. 2005

Nucleic Acids Research

305

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This work presents evidence that photo-excitation of guanine radical cations results in high yields of deoxyribose sugar radicals in DNA, guanine deoxyribonucleosides and deoxyribonucleotides. In dsDNA at low temperatures, formation of C1′• is observed from photo-excitation of G•+ in the 310–480 nm range with no C1′• formation observed ≥520 nm. Illumination of guanine radical cations in 2′dG, 3′-dGMP and 5′-dGMP in aqueous LiCl glasses at 143 K is found to result in remarkably high yields (∼85–95%) of sugar radicals, namely C1′•, C3′• and C5′•. The amount of each of the sugar radicals formed varies dramatically with compound structure and temperature of illumination. Radical assignments were confirmed using selective deuteration at C5′ or C3′ in 2′-dG and at C8 in all the guanine nucleosides/tides. Studies of the effect of temperature, pH, and wavelength of excitation provide important information about the mechanism of formation of these sugar radicals. Time-dependent density functional theory calculations verify that specific excited states in G•+ show considerable hole delocalization into the sugar structure, in accord with our proposed mechanism of action, namely deprotonation from the sugar moiety of the excited molecular radical cation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

UVA-visible photo-excitation of guanine radical cations produces sugar radicals in DNA and model structures

Adhikary

Malkhasian

Collins

et al. 2005

Nucleic Acids Research

305

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“…The reactions given below represent our current model for explaining end product formation based on the initial radicals. The model is based on a rather large body of work that has been presented previously (20) and reviewed recently (9,21,22). Two of the major base products, stemming from one-electron oxidation of the DNA base stack, are 8oxoGua and fapyGua (23).…”

Section: Introductionmentioning

confidence: 99%

On the Chemical Yield of Base Lesions, Strand Breaks, and Clustered Damage Generated in Plasmid DNA by the Direct Effect of X Rays

2007

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The purpose of this study was to determine the yield of DNA base damages, deoxyribose damage, and clustered lesions due to the direct effects of ionizing radiation and to compare these with the yield of DNA trapped radicals measured previously in the same pUC18 plasmid. The plasmids were prepared as films hydrated in the range 2.5 < Γ < 22.5 mol water/mol nucleotide. Single-strand breaks (SSBs) and double-strand breaks (DSBs) were detected by agarose gel electrophoresis. Specific types of base lesions were converted into SSBs and DSBs using the base-excision repair enzymes endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg). The yield of base damage detected by this method displayed a strikingly different dependence on the level of hydration (Γ) compared with that for the yield of DNA trapped radicals; the former decreased by 3.2 times as Γ was varied from 2.5 to 22.5 and the later increased by 2.4 times over the same range. To explain this divergence, we propose that SSB yields produced in plasmid DNA by the direct effect cannot be analyzed properly with a Poisson process that assumes an average of one strand break per plasmid and neglects the possibility of a single track producing multiple SSBs within a plasmid. The yields of DSBs, on the other hand, are consistent with changes in free radical trapping as a function of hydration. Consequently, the composition of these clusters could be quantified. Deoxyribose damage on each of the two opposing strands occurs with a yield of 3.5 ± 0.5 nmol/J for fully hydrated pUC18, comparable to the yield of 4.1 ± 0.9 nmol/J for DSBs derived from opposed damages in which at least one of the sites is a damaged base.

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“…The irradiation of cells in the presence of various radical scavengers has shown that cell killing is strongly correlated with one product of water radiolysis, the hydroxyl radical ( • OH) (Roots andOkada 1975, Dahm-Daphi et al 2000). Particular emphasis is placed on the importance of the reaction of this species with DNA (Bernhard and Close 2003). Therefore we have been investigating the reactivity of • OH with DNA in model systems.…”

Section: Introductionmentioning

confidence: 99%

Kinetic behavior of the reaction between hydroxyl radical and the SV40 minichromosome

Aguilera

Milligan

2007

Radiation Physics and Chemistry

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Aqueous solutions containing the minichromosomal form of the virus SV40 and the radical scavenger DMSO were subjected to gamma-irradiation, and the resulting formation of single strand breaks (SSB) was quantified. Under the irradiation conditions, most SSBs were produced as a consequence of hydroxyl radical ( • OH) reactions. By controlling the competition between DMSO and the viral DNA substrate for • OH, we are able to estimate the rate coefficient for the reaction of • OH with the SV40 minichromosome. The results cannot be described adequately by homogeneous competition kinetics, but it is possible to describe the rate coefficient for the reaction as a function of the scavenging capacity of the solution. The experimentally determined rate coefficient lies in the range 1×10 9 -2×10 9 L mol −1 s −1 at 10 7 s −1 , and increases with increasing scavenging capacity.

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DNA Damage Dictates the Biological Consequences of Ionizing Irradiation

Cited by 43 publications

References 158 publications

UVA-visible photo-excitation of guanine radical cations produces sugar radicals in DNA and model structures

UVA-visible photo-excitation of guanine radical cations produces sugar radicals in DNA and model structures

On the Chemical Yield of Base Lesions, Strand Breaks, and Clustered Damage Generated in Plasmid DNA by the Direct Effect of X Rays

Kinetic behavior of the reaction between hydroxyl radical and the SV40 minichromosome

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