Copper, Iron and Ionizing radiation causing DNA damage

Hydrogen peroxide is an important reactive oxygen species (ROS) that arises either during the aerobic respiration process or as a by-product of water radiolysis after exposure to ionizing radiation.

The reaction of hydrogen peroxide with transition metals imposes on cells an oxidative stress condition that can result in damage to cell components such as proteins, lipids and principally to DNA, leading to mutagenesis and cell death.

Escherichia colicells are able to deal with these adverse events via DNA repair mechanisms, which enable them to recover their genome integrity. These include base excision repair (BER), nucleotide excision repair (NER) and recombinational repair.

Other important defense mechanisms present in Escherichia coli are OxyR and SosRS anti-oxidant inducible pathways, which are elicited by cells to avoid the introduction of oxidative lesions by hydrogen peroxide.

This review summarizes the phenomena of lethal synergism between UV irradiation (254 nm) and H2O2, the cross-adaptive response between different classes of genotoxic agents and hydrogen peroxide, and the role of copper ions in the lethal response to H2O2 under low-iron conditions.

Copper and Hydrogen Peroxide

Oxidative DNA damage may play an important role in human disease including cancer.

Previously, mutational spectra have been determined using systems that include transition metal ions and hydrogen peroxide (H2O2).

G→T transversions and C→T transitions were the most common mutations observed including some CC→TT tandem mutations. C→T transition mutations at methylated CpG dinucleotides are the most common mutations in human genetic diseases. It has been hypothesized that oxidative stress may increase the frequency of mutations at methylated CpG sequences. Here we have used a CpG-methylated shuttle vector to derive mutational spectra of copper/H2O2-induced DNA damage upon passage of the shuttle vector through human fibroblasts.

We find that copper/H2O2 treatment produces higher numbers of CpG transition mutations when the CpGs are methylated but does not create clear C→T hotspots at these sites.

More strikingly, we observed that this treatment produces a substantial frequency of mutations that were mCG→TT tandem mutations. Six of seven tandem mutations were of this type. mCG→TT mutations (6/63 = 10% of all mutations) were observed only in nucleotide excision repair-deficient (XP-A) cells but were not found in repair-proficient cells.

The data suggest that this novel type of mutation may be produced by vicinal or cross-linked base damage involving 5-methylcytosine and a neighboring guanine, which is repaired by nucleotide excision repair. We suggest that the underlying oxidative lesions could be responsible for the progressive neurodegeneration seen in XP-A individuals.

DNA damage induced by reactive oxygen species (ROS) is an important intermediate in the pathogenesis of human conditions such as cancer and aging (15).

ROS-induced DNA damage products are both mutagenic and cytotoxic.

Hydrogen peroxide (H2O2), which generates hydroxy radicals in the presence of transition metal ions, is considered an appropriate model for ROS.

H2O2 is produced endogenously by several physiological processes, e.g. during oxidative phosphorylation (6) and by the inflammatory cell respiratory burst (7).

Because it is freely diffusible, H2O2 can potentially reach the nucleus to interact with DNA (8). H2O2 causes strand breaks (9) and base damage (10,11) in DNA by a mechanism that requires transition metal ions, such as iron or copper (1214). Mixtures of Cu(II) ions and H2O2, often with added ascorbic acid, produce extensive strand breaks in DNA (1517). Strand breaks often occur near guanine residues, and it has been suggested that copper ions bind to DNA at these sites (15). Indeed, Cu(II)-dependent DNA fragmentation has been reported to be much more extensive than that produced by equimolar Fe(III) ions in comparable reaction mixtures (16,18,19). Cu(II)/ascorbate/H2O2-mediated DNA damage in aerobic aqueous solutions is believed to be induced in vitro and in vivo through formation of a DNA–Cu(I)–H2O2 complex (16,2022). DNA damage induced by copper/H2O2 is enhanced by packaging of DNA into nucleosomes (23).

Exposure of target cells to H2O2 reproduces at least some components of the known endogenous DNA damage spectrum.

More than 30 different sugar and base modifications have been identified (11). Levels of oxidative DNA damage products have been measured in tissues by a variety of techniques and, although there is some controversy about the ‘true’ level of oxidative DNA damage, the levels can be quite substantial (24,25).

It is unclear which of the many different lesions produced by DNA oxidation is the one most responsible for inducing mutations. The mutations that are produced depend on the source of the ROS and the particular experimental system used to study the mutations.


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connie dello buono

Health educator, author and enterpreneur or ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at and posts in this site.

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