The sacrificial role of easily oxidizable sites in the protection of DNA from damage

Abstract

It has been suggested that DNA contains sacrificial nucleobase sequences that protect sensitive regions of the genome from oxidative damage. Oxidation of DNA by loss of an electron generates a radical cation that can migrate long distances by hopping. The radical cation can be trapped irreversibly at certain sites (GG steps) by reaction with H2O or O2 leading to the formation of lesions (oxidative damage). A series of DNA oligomers that contain regularly spaced GG steps and an 8-oxo-7,8-dihydroguanine (8-oxoG), which serves as a proxy for possibly sacrificial protective low oxidation potential sites, was prepared and analyzed. We find that in certain special sequences of DNA nucleobases that 8-oxoG protects remote GG steps from oxidative damage but that this is not a general phenomenon extending to normal mixed sequence DNA. This is a consequence of the change in the relative rate of charge hopping compared with trapping of the radical cation. When hopping is relatively slow, 8-oxoG exerts no protective effect. Thus, it seems unlikely that low oxidation potential sequences play a meaningful part in protecting mixed sequence DNA from damage.

8-oxoG DNA Glycosylase-1 Inhibition Sensitizes Neuro-2a Cells to Oxidative DNA Base Damage Induced by 900 MHz Radiofrequency Electromagnetic Radiation

“…Within the structure of DNA, DNA bases are considered to be highly sensitive to ROS oxidation, and guanine is particularly susceptible to ROS-induced modification because of its low redox potential [51]. Therefore, we speculated that DNA bases, particularly purines, might be more sensitive to low-energy RF-EMFs radiation than DNA strands.…”

Oxidative damage to DNA: Inhibition of guanine damage

“…Less common nucleobases, such as 8-OxoG, can have a much lower oxidation potential than guanine, and they have been found to act as deep traps [9,19] for radical cations. Surprisingly, it has recently been found that one-electron oxidation of DNA sequences that lack guanines leads to reaction at thymines, which has a high oxidation potential [10].…”

“…7. In DNA (5) and DNA (6), the charge migration through AA bridges is much faster than is its consumption at a GG step [18,19]. However, the radical cation is irreversibly consumed the first time it encounters an 8-oxoG, and thus no reaction is detected at any other nucleobase in the oligomer.…”

“…Similar protection of guanine nucleobases is obtained when AA bridges are replaced by AT bridges. However, the introduction of a greater barrier to the radical cation migration such as ATTA bridge reduces the protective effect that 8-oxoG has on the preceding GG steps [19]. …”

Telomeric D-loops Containing 8-Oxo-2′-deoxyguanosine Are Preferred Substrates for Werner and Bloom Syndrome Helicases and Are Bound by POT1

“…The results demonstrate that WRN and BLM preferentially unwind telomeric D-loops containing 8-oxodG. It is important to point out that the 8-oxodG-containing D-loops used in this study, DL2-4, contain one (DL2) or two (DL3, DL4) 8-oxodG residues and are predicted to have the identical stability and melting temperature as DL1, which contains no damage, and to lack any gross structural perturbation in the vicinity of the 8-oxodG residues (43,44). This is consistent with our observations that DL1-4 are equally resistant to MBN digestion (Fig.…”