Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair
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DNA methylation is a major epigenetic mechanism for gene silencing. Whereas 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.
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TET-catalyzed oxidation of 5mC followed by decarboxylation or base excision is strongly suspected to contribute to DNA demethylation.
“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 DNA methylation patterns in somatic cells (Figueroa et al., 2010; Ko et al., 2010; Yamazaki et al., 2012).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Cortellino et al., 2011
TET-dependent active DNA demethylation is supported by recent evidence.
“Recent evidences support a role for TET-dependent active DNA demethylation process [42,43].”
From PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation (2013) · cites this paper as [43]
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- Authors
- Cortellino, S., Xu, J., Sannai, M., Moore, R., Caretti, E., Cigliano, A., Le Coz, M., Devarajan, K., Wessels, A., Soprano, D., Abramowitz, L. K., Bartolomei, M. S., Rambow, F., Bassi, M. R., Bruno, T., Fanciulli, M., Renner, C., Klein-Szanto, A. J., Matsumoto, Y., Kobi, D., Davidson, I., Alberti, C., Larue, L., & Bellacosa, A.
- Affiliations
- Fox Chase Cancer Center (US)
- Medical University of South Carolina (US)
- Temple University (US)
- University of Pennsylvania (US)
- Centre National de la Recherche Scientifique (FR)
- Instituto Nazionale Tumori Regina Elena (IT)
- East Stroudsburg University (US)
- Corresponding author
- Bellacosa, Alfonso
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 146
- Issue
- 1
- Pages
- 67-79
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3230223
- OpenAlex
- W2062211740
- Cited by
- 809
- References
- 80
- Citations by year
- 2026: 20 · 2025: 24 · 2024: 21 · 2023: 33 · 2022: 29 · 2021: 32 · 2020: 32 · 2019: 39 · 2018: 46 · 2017: 59 · 2016: 64 · 2015: 76 · 2014: 95 · 2013: 107 · 2012: 99
- FWCI
- 43.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 747 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Funders
- National Cancer Institute (R29CA078412, R01CA078412, CA78412, P30CA006927, CA06927)
- National Institute of General Medical Sciences (T32GM008216)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK067558, R01DK067558)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- thymine DNA glycosylase, DNA demethylation, AID, GADD45A, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, P300, retinoic acid, CpG islands, embryonic lethality, enhancers, epigenetic regulation, DNA repair
- MeSH terms
- GADD45 Proteins, AICDA (Activation-Induced Cytidine Deaminase), Animals, Cytidine Deaminase, Cytosine, Female, Male, Mice, Inbred C57BL, Nuclear Proteins, Promoter Regions, Genetic, Transcription, Genetic, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Cycle Proteins, DNA Methylation, Thymine DNA Glycosylase, 5-Methylcytosine, Embryonic Development, Mice, Gene Knock-In Techniques
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