Which DNA damage is likely to be relevant in hormetic responses?

Abstract

Working under the assumption that hormesis is triggered by specific types of DNA damage, this report focuses on the types of damage which form the signature of ionizing radiation. The key attribute of the signature is the clustering of damage, arising from clusters of energy deposition such that more than one site within a 10 base pair segment of DNA has been chemically altered. A brief overview is given on what is currently believed to be the primary components of clustered damage produced by the direct effect. The overview draws primarily on studies that utilize electron paramagnetic resonance to measure free radical intermediates and gel electrophoresis to measure clustered damage in plasmid DNA. Based on this information, the threshold for a radiation induced biological response is calculated.

Keywords: DNA damage; Direct effect; Plasmid DNA; Radiation chemistry; Radiation products.

FIGURE 1

DNA in aqueous solution. Cartoon showing the intersection of an ionizing radiation track with DNA, the solvation shell of DNA, and the bulk water in the vicinity of DNA. The solid dots represent energy deposition events, i.e., ionization and excitation. Ionization of bulk water yields the water radical cation, H₂O^+•, and the aqueous electron, e⁻_aq, which may react with DNA giving indirect-type damage. Ionization of DNA and its solvation shell results in direct-type damage. The DNA solvation shell consists of up to ~20 to 22 waters/nucleotide.

FIGURE 2

Initial radical ion distribution. A model showing the distribution of radical ions initially formed by direct ionization of DNA. The model is based primarily on EPR experiments. Further detail is given in Figures 4–6 and chemical structures are given in Figure 3.

FIGURE 3

Chemical structures and notation used in the text.

FIGURE 4

The deoxyribose radical cation, dRib^+•, deprotonates from any of the five deoxyribose carbons. Shown here is an example of the reactions stemming from C1′ deprotonation.

FIGURE 5

The reaction pathway leading to the formation of 8-oxo-guanine starting from the guanine radical cation, Gua^+•.

FIGURE 6

The reaction pathways leading to 5,6-dihydrothymine, DHThy, and 5,6-dihydrouracil, DHUra, starting from the respective one-electron reduced pyrimidines, Thy^−• and Cyt^−•.