TdgEdit
TDG, short for thymine-DNA glycosylase, is a DNA repair enzyme that also plays a central role in epigenetic remodeling. Encoded by the TDG gene in humans and many other vertebrates, this enzyme belongs to the base excision repair (BER) family of glycosylases. Its primary job is to recognize and remove inappropriate or damaged bases from DNA, initiating a repair process that preserves genome integrity and helps shape the epigenetic landscape across development and differentiation.
In mammals, TDG is notable for two interlinked activities. First, it excises thymine when it appears opposite guanine in G•T mispairs, a common result of spontaneous deamination of 5-methylcytosine or chemical insult. Second, and more broadly impactful, TDG participates in active DNA demethylation by targeting oxidized forms of methylcytosine—such as 5-formylcytosine and 5-carboxylcytosine—that are generated by TET family enzymes. After TDG removes these bases, downstream repair processes eventually replace them with unmodified cytosine, contributing to dynamic epigenetic reprogramming in cells. These dual roles—maintaining DNA sequence fidelity and enabling epigenetic flexibility—make TDG a key node linking genome maintenance with gene regulation.
Structure and mechanism
TDG belongs to the helix-hairpin-helix glycosylase domain superfamily and operates via the classical BER pathway. The enzyme recognizes damaged or mispaired bases, flips the target base out of the DNA double helix into its active site, and cleaves the N-glycosidic bond to generate an abasic (AP) site. The resulting AP site is then processed by AP endonucleases and the remaining BER machinery to restore the DNA backbone with a correct base. Structural and biochemical studies highlight a catalytic pocket that accommodates thymine and oxidized cytosines, as well as a flexible surface that supports interactions with other BER factors and histone-binding partners. For readers seeking the molecular details, see discussions of base excision repair and glycosylase domains, as well as the specific substrate recognition features that enable TDG to target both thymine and 5mC derivatives. base excision repair Thymine-DNA glycosylase.
TDG operates in concert with other components of the repair and chromatin remodeling networks. Its activity is coordinated with AP endonucleases such as APE1 and various polymerases to complete the restoration of the DNA sequence. The enzyme’s access to DNA is also influenced by chromatin state and histone modifications, linking DNA repair to the regulation of gene expression. For broader context on how DNA repair integrates with chromatin control, see chromatin and DNA damage response.
Biological roles
DNA repair
TDG contributes to genome stability by removing thymine from G•T mispairs that arise through deamination or other insults, thereby preventing C•G to T•A transitions from accumulating in the genome. This activity is essential for maintaining accurate genetic information, especially in tissues with high metabolic rates and active cell turnover. In the BER pathway, TDG’s base excision creates an abasic site that is subsequently processed to restore the correct base. TDG also helps to correct other subtle mispairs and lesions, reflecting its broader role in keeping the DNA code intact. For readers exploring the repair landscape, see base excision repair and DNA polymerase pathways.
Epigenetic remodeling and demethylation
Beyond repairing bases, TDG participates in active DNA demethylation, a process critical for reprogramming cell identity during development and in response to environmental cues. TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine; TDG excises the latter two, enabling replacement with cytosine through BER. This mechanism links epigenetic marks to the DNA repair machinery, allowing dynamic adjustments of gene expression without altering the underlying genetic sequence. For broader reading on the epigenetic cycle, consult 5-methylcytosine and TET enzymes.
Development, disease, and aging
TDG activity influences developmental programs and tissue-specific gene expression patterns through its epigenetic role. Aberrations in TDG function or regulation can disrupt precise epigenetic reprogramming, with potential consequences for development and cellular differentiation. In humans, alterations in TDG expression or activity have been studied in the context of cancer and inflammatory diseases, where epigenetic misregulation often accompanies malignant transformation. Research continues to clarify the extent to which TDG contributes to disease phenotypes and whether it represents a viable target for therapeutic intervention. For a broader view of how DNA repair intersects with disease, see cancer biology and epigenetics.
Regulation and interactions
TDG activity is modulated by cellular context, including post-translational modifications and interactions with other proteins. The enzyme forms complexes with components of the BER machinery and with factors involved in chromatin remodeling, which helps it access DNA in the crowded chromatin environment. Its cooperation with TET enzymes in demethylation pathways underscores a coordinated network that connects DNA repair with epigenetic regulation. For readers interested in protein networks and regulation, see post-translational modification and protein–protein interaction.
Evolution and distribution
TDG homologs are found across a broad range of vertebrates and in some invertebrates, reflecting an evolutionarily conserved need to monitor cytosine methylation status and to repair deaminated bases. While the precise substrate preferences and regulatory partnerships vary among species, the core function of recognizing and excising aberrant bases within the DNA helix remains a common theme. For readers seeking a comparative perspective, see evolution of enzymes and DNA repair across taxa.