DNA Damage: 8-oxo-guanine
In its most general sense, the central dogma of molecular biology states that genetic information is passed from DNA to RNA to proteins. It therefore holds that as the carrier of genetic information in cells, the integrity of DNA is highly important for normal cell survival and function. Changes in DNA sequence can lead to the production of aberrant proteins, causing cell death or altered cell function. Sometimes these changes in function can be serious enough to cause tumorogenesis. Despite its stability to damaging processes such as hydrolytic cleavage, DNA is not immune to oxidative damage, much of which results from reaction with reactive oxygen species. Reactive oxygen species are generated as a result of normal cellular metabolism. Although antioxidants and specific enzymes dedicated to the purpose are able to scavenge many of these ROS, some of them persist long enough to react with DNA. As Guanine has the lowest oxidation potential of all of the DNA bases (Steenken 1997), it is the most susceptible to oxidative damage. Oxidation at the C8 position can give the product 8-oxo-guanine.
Instead of hydrogen bonding with cytosine as guanine normally does, it can form a Hoogsteen base pair with adenine (shown above). Therefore, during DNA replication, DNA polymerase may mistakenly insert an adenosine opposite an 8-oxo-dG, resulting in a stable change in DNA sequence, a process known as mutagenesis.
Edit: My previous phrasing “…resulting in a change in DNA sequence that can potentially be mutagenic” was mistaken. It was meant to imply that this change in DNA sequence, depending on its location, may or may not have an effect on amino acid sequence or gene expression. Therefore, the cell may or may not be affected. However, to clarify, a change in DNA sequence is, by definition, mutagenic.
Stay tuned for future posts on oxidative DNA damage!
Steenken, S.; Jovanovic, S. V. J. Am. Chem. Soc. 1997, 119, 617-618
Greenberg, M. M.; Chem Res Toxicol, 1998. 11, 1235-1248