DNA Damage: Causes and Effects

The most significant consequence of oxidative stress in the body is thought to be damage to DNA.  DNA may be modified in a variety of ways, which can ultimately lead to mutations and genomic instability. This could result in the development of a variety of cancers including colon, breast, and prostate. Here we discuss the various types of damage to DNA, including oxidative damage, hydrolytic damage, DNA strand breaks, and others.

Oxidative DNA damage refers to the oxidation of specific bases. 8-hydroxydeoxyguanosine (8-OHdG) is the most common marker for oxidative DNA damage and can be measured in virtually any species. It is formed and enhanced most often by chemical carcinogens. A similar oxidative damage can occur in RNA with the formation of 8-OHG (8-hydroxyguanosine), which has been implicated in various neurological disorders.

Hydrolytic DNA damage involves deamination or the total removal of individual bases. Loss of DNA bases, known as AP (apurinic/apyrimidinic) sites, can be particularly mutagenic and if left unrepaired they can inhibit transcription. Hydrolytic damage may result from the biochemical reactions of various metabolites as well as the overabundance of reactive oxygen species.

Ultraviolet and other types of radiation can damage DNA in the form of DNA strand breaks. This involves a cut in one or both DNA strands; double-strand breaks are especially dangerous and can be mutagenic, since they can potentially affect the expression of multiple genes. UV-induced damage can also result in the production of pyrimidine dimers, where covalent cross-links occur in cytosine and thymine residues. The most common pyrimidine dimers are cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP). CPD and 6-4PP are the most frequent DNA mutations found in the p53 protein in skin cancers. Pyrimidine dimers can disrupt polymerases and prevent proper replication of DNA.

DNA damage may also result from exposure to polycyclic aromatic hydrocarbons (PAHs). PAHs are potent, ubiquitous atmospheric pollutants commonly associated with oil, coal, cigarette smoke, and automobile exhaust fumes. A common marker for DNA damage due to PAHs is Benzo(a)pyrene diol epoxide (BPDE). BPDE is found to be very reactive, and known to bind covalently to proteins, lipids, and guanine residues of DNA to produce BPDE adducts. If left unrepaired, BPDE-DNA adducts may lead to permanent mutations resulting in cell transformation and ultimately tumor development.

The Comet Assay, or single cell gel electrophoresis assay (SCGE), is a common technique used to measure all types of DNA damage, including the various types of damage mentioned above. It is a convenient tool for measuring universal DNA damage in individual cells.