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. 2020 Jun 17;7(4):1768819.
doi: 10.1080/23723556.2020.1768819. eCollection 2020.

TDG is a novel tumor suppressor of liver malignancies

Haider M Hassan  1   2 , Majdina Isovic  1   2 , Michael Tully Underhill  3 , Joseph Torchia  1   2
Affiliations

TDG is a novel tumor suppressor of liver malignancies

Haider M Hassan et al. Mol Cell Oncol. .

Abstract

In a recent publication, we demonstrated that conditional deletion of the gene encoding thymine DNA glycosylase (TDG) leads to a late onset of hepatocellular carcinoma (HCC). TDG loss causes disruption in active DNA demethylation in the liver and dysregulation of the farnesoid X receptor and small heterodimer partner (FXR-SHP) regulatory cascade. This leads to a loss of bile acid and glucose homeostasis, which predisposes mice to HCC.

Keywords: FXR; SHP; Thymine DNA Glycosylase; active DNA demethylation; bile acid; glucose intolerance; hepatocellular carcinoma; liver cancer; ten eleven translocation.

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Figures

Figure 1.
Figure 1.
Mechanism of active DNA demethylation by FXR/TDG signaling. In the absence of ligand, the small heterodimer partner (Shp) promoter is hypermethylated and is repressed due in part to the binding of DNA methyltransferase 3A (DNMT3A). Binding of GW4064 (A bile acid receptor agonist) ligand to farnesoid X receptor (FXR) activates the FXR and retinoid X receptor (RXR) heterodimer which causes the assembly of thymine DNA glycosylase (TDG), ten eleven translocase 2 (TET2) and CREB-binding protein (CBP) to the FXR response element (FXRE) at the Shp locus. TET/TDG activities are coupled and act in concert to oxidize 5-methylcytosine (5-mC) to 5-formylcytosine (5-fC) or 5-carboxylcytosine (5-caC) followed by excision. The excised intermediates trigger recruitment of the base excision repair (BER) machinery to restore unmethylated DNA. The conditional deletion of Tdg in mice leads to a higher basal level of 5-fC/5-caC at Shp. In addition, co-activator complex assembly and active DNA demethylation at Shp in response to GW4064 are blocked, thereby, leading to a loss of Shp expression.
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References

    1. Kohli RM, Zhang Y.. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502:44–46. doi:10.1038/nature12750. - DOI - PMC - PubMed
    1. Cortázar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E, Wirz A, Schuermann D, Jacobs AL, Siegrist F, et al. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011;470(7334):419–423. doi:10.1038/nature09672. - DOI - PubMed
    1. Shen L, Wu H, Diep D, Yamaguchi S.. Genome-wide analysis reveals TET-and TDG-dependent 5-methylcytosine oxidation dynamics. Cell. 2013;153(3):692–706. doi:10.1016/j.cell.2013.04.002. - DOI - PMC - PubMed
    1. Hassan HM, Kolendowski B, Isovic M, Bose K, Dranse HJ, Sampaio AV, Underhill TM, Torchia J. Regulation of active DNA demethylation through RAR-mediated recruitment of a TET/TDG complex. Cell Rep. 2017;19(8):1685–1697. doi:10.1016/j.celrep.2017.05.007. - DOI - PubMed
    1. Xu J, Cortellino S, Tricarico R, Chang W-C, Scher G, Devarajan K, Slifker M, Moore R, Bassi MR, Caretti E. Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression. Oncotarget. 2017;8(52):89988–89997. doi:10.18632/oncotarget.21219. - DOI - PMC - PubMed

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