8-Oxoguanine

8-Oxoguanine (also known as 8-hydroxyguanine) is a modified base that occurs in DNA as a result of damage by oxidative stress. It is one of the most common and mutagenic DNA lesions caused by reactive oxygen species (ROS). The presence of 8-oxoguanine in DNA can lead to mutations, as it pairs with Adenine as well as Cytosine, leading to G:C to T:A transversions during DNA replication. The repair of 8-oxoguanine is crucial for maintaining genetic stability and preventing the development of cancer.

Formation and Effects

8-Oxoguanine forms when guanine in DNA reacts with reactive oxygen species, such as hydroxyl radicals produced by radiation or cellular metabolic processes. This lesion can miscode during replication, pairing with adenine instead of cytosine, leading to a G:C to T:A transversion mutation. These mutations can contribute to the onset and progression of various cancers and age-related diseases.

Detection and Repair

Cells have developed mechanisms to repair 8-oxoguanine lesions to maintain genomic integrity. The base excision repair (BER) pathway is primarily responsible for correcting these lesions. The human OGG1 (8-oxoguanine DNA glycosylase) enzyme is a key component of this pathway, recognizing and excising 8-oxoguanine from DNA. Following excision, the AP site (apurinic/apyrimidinic site) left behind is further processed by BER enzymes, restoring the original DNA sequence.

Clinical Significance

The accumulation of 8-oxoguanine in DNA is associated with an increased risk of cancer and is considered a biomarker for oxidative stress and carcinogenesis. Studies have shown that individuals with defects in the 8-oxoguanine repair pathway, such as mutations in the OGG1 gene, have a higher susceptibility to cancer. Furthermore, the level of 8-oxoguanine lesions in DNA has been proposed as a potential indicator of the efficacy of antioxidant therapies.

Research Applications

8-Oxoguanine is also used as a tool in molecular biology and genetic research to study the mechanisms of DNA damage and repair. It serves as a model lesion for understanding how cells respond to oxidative DNA damage and the role of this damage in disease processes.