Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair

By S. Cortellino, Jinfei Xu, Mara Sannai, Robert Moore, Elena Caretti, A. Cigliano, M. L. Coz, Karthik Devarajan, A. Wessels, D. Soprano and 14 more. Nature reviews. Molecular cell biology, 2011

808 citations recorded by the source corpus.

Summary DNA methylation is a major epigenetic mechanism for gene silencing. While methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether an active demethylating activity is involved. Here we show that either knockout or catalytic inactivation of the DNA repair enzyme Thymine DNA Glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific, developmentally- and hormonally-regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage-response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b31a8077acd824b34fc26229057c7ba9c740dfb2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Wolf Reik
2. Yi Zhang
3. W. Dean
4. Jörn Walter
5. Hao Wu
6. Fátima Santos
7. S. Baylin
8. Peter A. Jones

In Molecular Biology

1. Yi Zhang
2. Hao Wu
3. Peter A. Jones
4. Wolf Reik
5. S. Baylin
6. W. Dean
7. Jörn Walter
8. Felix Krueger

Citations in the corpus

• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “In agreement with this, although AID may contribute to active PGC demethylation in vivo (Popp et al. 2010), it is probably responsible for only a small portion of this large-scale demethylation process, as substantial demethylation still occurs in the absence of AID.”
• Uncovering the role of 5-hydroxymethylcytosine in the epigenome (2011, background): “Furthermore, both single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) and TDG glycosylases have strong activity towards 5hmU:G mismatches and appear to be involved in this pathwa”
• Influence of Metabolism on Epigenetics and Disease (2013, neutral): “TET-catalyzed oxidation of 5mC followed by decarboxylation or base excision is strongly suspected of contributing to DNA demethylation (Cortellino et al., 2011; He et al., 2011; Ito et al., 2011), yet there are currently conflicting reports regarding the effect of TET inactivation on global DNAmethy”
• The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells (2012, background): “…mechanisms involving factors such as Aid and Tdg have been shown to play a role in DNA methylation reprogramming in PGCs (Popp et al., 2010; Cortellino et al., 2011), suggesting that active and passive mechanisms of demethylation work in concert to ensure robust epigenetic reprogramming in…”
• MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system (2013, neutral): “types (Cortellino et al., 2011; Ito et al., 2011).”
• DNA Demethylation Dynamics (2011, background): “In mammals, the process is more complex, as no glycosylases have been identified that act directly on 5mC or 5hmC. Recently, an intermediate step, deamination, has been suggested to precede BER in mammalian DNA demethylation (Cortellino et al., 2011; Guo et al., 2011).”
• A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “Current evidence is that this is not solely due to the formation of 5-hydroxymethylcytosine, which instead may be an intermediate that must subsequently be converted to cytosine through the action of the DNA repair processes that are mediated by proteins such as activation-induced cytidine deaminase”
• DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, background): “However, it is likely that the hypermethylation occurs prior to PGC specification, as de novo DNA methylation is repressed in PGCs (Cortellino et al. 2011).”
• DNA Methylation and Its Basic Function (2013, background): “…all the mentioned mechanisms of active DNA demethylation, the BER pathway uses thymine DNA glycosylase (TDG) to cleave off the modified residueF thymine, 5-hydroxymethyl-uracil, 5-formyl-cytosine, and 5-carboxy-cytosineFand replace it with a naked cytosine (Cortellino et al, 2011; He et al, 2011).”
• Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “This DNA modification is present at exceedingly low amounts in ESCs and is efficiently cleaved and repaired by the DNA glycosylases TDG and SMUG1 followed by BER (Cortellino et al. 2011; Pfaffeneder et al. 2014).”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “5 and exhibit modest increase in level of 5mC at some CpG-rich gene promoters (Cortázar et al., 2011; Cortellino et al., 2011).”