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.
Highlights
Cytosine and 5-methylcytosine (5mC) are intrinsically unstable in genomic DNA and have a tendency to spontaneously deaminate, generating thymine and uracil, respectively, which, if not removed from the G:T and G:U mismatches prior to replication, will lead to incorporation of adenine [1, 2]. 5mC is mostly located at palindromic CpG sequences, and this mechanism of CpG site mutagenesis by deamination is estimated to cause nearly one-third of all mutations in both cancer and human genetic diseases [3, 4]
We previously described the generation of mice bearing the inactive, null allele Tdg, in which Cremediated recombination between the loxP sites generates a deletion of exons 3 through 7 [10]
The combined results from our in vivo mouse studies and investigation of human cancer databases indicate a role of Thymine DNA Glycosylase (TDG) in the suppression of intestinal tumorigenesis, and in sex-specific protection from colorectal cancer (CRC)
Summary
Cytosine and 5-methylcytosine (5mC) are intrinsically unstable in genomic DNA and have a tendency to spontaneously deaminate, generating thymine and uracil, respectively, which, if not removed from the G:T and G:U mismatches prior to replication, will lead to incorporation of adenine [1, 2]. 5mC is mostly located at palindromic CpG sequences, and this mechanism of CpG site mutagenesis by deamination is estimated to cause nearly one-third of all mutations in both cancer and human genetic diseases [3, 4]. In addition to its role in genomic stability of CpG sites, TDG is required for active DNA demethylation during development; TDG balances the activity of DNA methyltransferases by maintaining CpG islands in their unmethylated state and promoting demethylation of tissuespecific, developmentally regulated enhancers [10, 11]. In this role in epigenomic stability, TDG acts downstream the Ten-Eleven Translocation (TET) family of dioxygenases in pathways of DNA demethylation initiated by iterative oxidation of 5mC to the novel cytosine species: 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylxytosine (5caC). It should be noted that a similar role of MBD4 in DNA demethylation has been proposed but remains controversial; whereas TDG is essential [10, 13], MBD4 is dispensable for mammalian development [9]
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