Thymine-DNA glycosylase

Thymine-DNA Glycosylase (TDG) is a crucial enzyme in the process of DNA repair and DNA demethylation. This enzyme plays a significant role in the maintenance of DNA methylation patterns, which are essential for regulating gene expression and maintaining genomic stability. TDG is involved in the Base Excision Repair (BER) pathway, where it recognizes and removes thymine or uracil from G:T or G:U mismatches within the DNA, which can arise through deamination of 5-methylcytosine or cytosine.

Function

TDG corrects G:T and G:U mismatches to G:C pairs, a process critical for the fidelity of DNA replication and repair. This correction mechanism is vital for preventing mutations that could lead to various diseases, including cancer. Moreover, TDG's role in DNA demethylation is essential for epigenetic reprogramming during development and in adult tissues, influencing gene expression patterns.

Mechanism

The enzyme operates by flipping the mismatched base out of the DNA helix and into its active site, where it cleaves the glycosidic bond between the base and the sugar-phosphate backbone, thus excising the erroneous base. Subsequently, the abasic site is repaired by other components of the BER pathway, restoring the correct DNA sequence.

Clinical Significance

Mutations in the TDG gene can lead to genomic instability and have been implicated in the development of certain cancers. Furthermore, as TDG is involved in epigenetic regulation, its dysfunction can affect gene expression, contributing to various diseases beyond cancer, including developmental disorders.

Research

Ongoing research is focused on understanding the detailed mechanisms of TDG's action, its interactions with other components of the DNA repair machinery, and its role in epigenetic regulation. This research has the potential to uncover new therapeutic targets for diseases caused by DNA repair defects and abnormal gene expression.

See Also

• DNA repair
• Epigenetics
• Base Excision Repair
• DNA methylation
• Genomic stability