The Role of Thymine DNA Glycosylase in Transcription, Active DNA Demethylation, and Cancer

SIMPLE SUMMARY: Thymine DNA Glycosylase (TDG) is a DNA repair protein that plays an important role in gene regulation. Recent studies have shown that TDG interacts with various transcription factors to activate target genes. TDG also functions in a pathway known as active DNA demethylation, which removes 5-mC from DNA and replaces it with unmethylated cytosine. In this review, we summarize the various functions of TDG in gene regulation as well as the physiological relevance of TDG in cancer. ABSTRACT: DNA methylation is an essential covalent modification that is required for growth and development. Once considered to be a relatively stable epigenetic mark, many studies have established that DNA methylation is dynamic. The 5-methylcytosine (5-mC) mark can be removed through active DNA demethylation in which 5-mC is converted to an unmodified cytosine through an oxidative pathway coupled to base excision repair (BER). The BER enzyme Thymine DNA Glycosylase (TDG) plays a key role in active DNA demethylation by excising intermediates of 5-mC generated by this process. TDG acts as a key player in transcriptional regulation through its interactions with various nuclear receptors and transcription factors, in addition to its involvement in classical BER and active DNA demethylation, which serve to protect the stability of the genome and epigenome, respectively. Recent animal studies have identified a connection between the loss of Tdg and the onset of tumorigenesis. In this review, we summarize the recent findings on TDG’s function as a transcriptional regulator as well as the physiological relevance of TDG and active DNA demethylation in cancer.