DNA-formamidopyrimidine glycosylase

DNA-formamidopyrimidine glycosylase (Fpg), also known as 8-oxoguanine DNA glycosylase, is an enzyme that in humans is encoded by the MUTYH gene. This enzyme plays a critical role in the base excision repair (BER) pathway of DNA repair. Fpg is particularly important for the removal of oxidative DNA damage, specifically, the repair of 8-oxoguanine, a mutagenic base byproduct produced by reactive oxygen species (ROS). The presence of 8-oxoguanine in DNA can lead to G:C to T:A transversion mutations, which are implicated in carcinogenesis, highlighting the significance of Fpg in maintaining genomic stability and preventing cancer.

Function

DNA-formamidopyrimidine glycosylase is involved in the cellular defense against oxidative DNA damage. It recognizes and excises oxidized purines, such as 8-oxoguanine and formamidopyrimidines, from damaged DNA. By cleaving the glycosidic bond between the damaged base and the deoxyribose sugar, it initiates the BER pathway. This action creates an abasic (apurinic/apyrimidinic or AP) site, which is then processed by other enzymes in the pathway, including AP endonuclease, DNA polymerase, and DNA ligase, to restore the DNA to its undamaged state.

Mechanism

The mechanism of action of Fpg involves several steps. First, the enzyme scans the DNA for damage. Upon encountering an oxidized purine, Fpg flips the damaged base out of the DNA helix and into its active site. This base flipping is critical for lesion recognition and removal. The enzyme then cleaves the N-glycosidic bond, releasing the damaged base and generating an AP site. Subsequent steps in the BER pathway repair the AP site, completing the repair process.

Clinical Significance

Mutations in the MUTYH gene, which encodes the Fpg enzyme, have been associated with MUTYH-associated polyposis (MAP), a condition characterized by the development of multiple adenomatous polyps in the colon and an increased risk of colorectal cancer. Individuals with MAP have a defective Fpg enzyme, leading to an accumulation of oxidative DNA damage and an increased mutation rate, which contributes to tumorigenesis. The study of Fpg and its associated pathways is crucial for understanding the molecular basis of cancer and developing potential therapeutic strategies.

Research

Research on DNA-formamidopyrimidine glycosylase continues to uncover its broader role in DNA repair, its interactions with other DNA repair proteins, and its potential as a target for cancer therapy. Studies have also focused on the development of inhibitors that can modulate the activity of Fpg for therapeutic purposes, particularly in cancer treatment where the regulation of DNA repair mechanisms can influence the sensitivity of cancer cells to chemotherapy and radiation therapy.

See Also

• Base excision repair
• Oxidative stress
• DNA repair
• MUTYH-associated polyposis
• Reactive oxygen species