Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression

Abstract

Thymine DNA Glycosylase (TDG) is a base excision repair enzyme that acts as a thymine and uracil DNA N-glycosylase on G:T and G:U mismatches, thus protecting CpG sites in the genome from mutagenesis by deamination. In addition, TDG has an epigenomic function by removing the novel cytosine derivatives 5-formylcytosine and 5-carboxylcytosine (5caC) generated by Ten-Eleven Translocation (TET) enzymes during active DNA demethylation. We and others previously reported that TDG is essential for mammalian development. However, its involvement in tumor formation is unknown. To study the role of TDG in tumorigenesis, we analyzed the effects of its inactivation in a well-characterized model of tumor predisposition, the ApcMin mouse strain. Mice bearing a conditional Tdgflox allele were crossed with Fabpl::Cre transgenic mice, in the context of the ApcMin mutation, in order to inactivate Tdg in the small intestinal and colonic epithelium. We observed an approximately 2-fold increase in the number of small intestinal adenomas in the test Tdg-mutant ApcMin mice in comparison to control genotypes (p=0.0001). This increase occurred in female mice, and is similar to the known increase in intestinal adenoma formation due to oophorectomy. In the human colorectal cancer (CRC) TCGA database, the subset of patients with TDG and APC expression in the lowest quartile exhibits an excess of female cases. We conclude that TDG inactivation plays a role in intestinal tumorigenesis initiated by mutation/underexpression of APC. Our results also indicate that TDG may be involved in sex-specific protection from CRC.

Active DNA demethylation—The epigenetic gatekeeper of development, immunity, and cancer

“…Conditional Tdg inactivation in Apc‐Min mice results in the increased frequency of small intestinal adenomas. Interestingly, this increase occurred in female mice, consistent with TCGA data showing that among colorectal cancer (CRC) cases, the lowest quartile of TDG and APC expression is associated with an excess of female cases 187 . As TDG has known interactions with an estrogen receptor, coupled with the fact that women with Lynch syndrome carry a higher lifetime risk of CRC, the connection between the estrogen hormone and colorectal oncogenesis may involve the demethylation machinery 188 .…”

Thymine DNA glycosylase as a novel target for melanoma

“…For conditional inactivation of Tdg in adult mice, we crossed Cre- ER T2 transgenic mice [33] (gift of Eric Brown) with Tdg flox/flox conditional knockout mice [50]. All the strains used have a nearly pure C57BL/6 genetic background (at least 10 backcrosses in this background).…”

<p>Berzosertib (VE-822) inhibits gastric cancer cell proliferation via base excision repair system</p>

“…For another uracil-DNA N-glycosylase, TDG (Thymine DNA Glycosylase) can act as thymine on G: T and G: U mismatches to protect CpG sites in the genome from deamination-induced mutagenesis. In addition, TDG is able to remove the novel cytosine derivatives, 5-formylcytosine and 5-carboxylcytosine, which are generated by TET (Ten-Eleven Translocation) enzymes during active DNA demethylation 26. However, when looking into other functions, TDG played a prominent role in oxidation and excision of 5Mc in DNA, thus controlling DNA demethylation 27,28.…”