Cited by 809Epigenetics and DNA MethylationDNA Repair MechanismsGenetic Syndromes and Imprinting

Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair

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Cortellino, Salvatore, Xu, Jinfei, Sannai, Mara, Moore, Robert, Caretti, Elena, Cigliano, Antonio, Le Coz, Madeleine, Devarajan, Karthik +16 more·2011·Cell

Abstract

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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Crossref · 10.1016/j.cell.2011.06.020

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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].”

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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
Venue
Cell
Publisher
Elsevier BV
Published
2011-07
Volume
146
Issue
1
Pages
67-79
ISSN
0092-8674 (ISSN-L)
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
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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