Abstract
Simple SummaryThymine 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.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.
Highlights
The methylation of cytosine at the 5th carbon (5-mC) is a prevalent form of DNA modification in mammals that is essential for various biological processes, such as Xchromosome inactivation, genomic imprinting, cell differentiation, and the suppression of mobile genetic elements [1]
Demethylation that is independent of the cell cycle. This process is dependent on the oxidative function of the ten eleven translocation (TET) family of proteins, of which there are three functional paralogs (TET1, TET2, and TET3) that exist in mammals due to a gene triplication event that occurred in jawed vertebrates [11,12]
The onset of liver cancer in TdgcKO mice was surprising considering that expression of Tdg is ubiquitous and is in stark contrast to Tet knockouts, which result in predominantly hematopoietic abnormalities and malignancies [60]
Summary
The methylation of cytosine at the 5th carbon (5-mC) is a prevalent form of DNA modification in mammals that is essential for various biological processes, such as Xchromosome inactivation, genomic imprinting, cell differentiation, and the suppression of mobile genetic elements [1]. 5-mC can be removed in a process called active DNA demethylation that is independent of the cell cycle Rather, this process is dependent on the oxidative function of the ten eleven translocation (TET) family of proteins, of which there are three functional paralogs (TET1, TET2, and TET3) that exist in mammals due to a gene triplication event that occurred in jawed vertebrates [11,12]. 5-fC and 5-caC are recognized and excised by the base excision repair (BER) protein Thymine DNA Glycosylase (TDG) This generates an apurinic/apyrimidinic (AP) site [13], which is repaired by the combined actions of AP endonuclease 1, DNA Polymerase β and XRCC1-DNA Ligase IIIα complex [14]. The goal of this review is to provide the reader with an overview of the mechanistic work that has been documented on the role of TDG in gene regulation as a framework for understanding its physiological relevance in cancer (a list of all the abbreviations used in this review can be found at the end of the main text)
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