Factors that cause DNA Damage

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DNA damage occurs continuously as a result of many factors included intracellular metabolism, replication, and exposure to genotoxic agents, such as ionizing radiation and chemotherapy and many others. If left unrepaired, this damage could result in changes or mutations within the cell genomic material. There are a number of different pathways that the cell can utilize to repair these DNA breaks. As DNA damage occurs within the chromatin, we postulate that modifications of histones are important for signaling the position of DNA damage, recruiting the DNA repair proteins to the site of damage, and creating an open structure such that the repair proteins can access the site of damage.

DNA damage from endogenous and exogenous sources threatens the genome and the epigenome, requiring chromatin-based DNA damage response pathways (DDR) to operate within structurally and functionally diverse chromatin environments. DDR pathways are essential for sensing, processing and repairing DNA damage.

It 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. 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.

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 stop transcription. Hydrolytic damage may result from the biochemical reactions of certain 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 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.

The damaging agents acting on DNA by virtue of their physical properties are, for example, short-wavelength electromagnetic energy such as ultraviolet (UV) radiation and ionizing radiation. Under specific conditions, low-energy electromagnetic waves, such as infrared radiation (heat) and microwave and radio wave radiation may also cause DNA damage. Among DNA damaging agents of chemical nature prominent are alkylating agents, oxidizing agents, chemicals creating DNA-DNA or DNA-protein crosslinks, and others.

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