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

Cell | Jul 8, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21722948

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.

Pubmed ID: 21722948 RIS Download

Mesh terms: 5-Methylcytosine | Animals | Cell Cycle Proteins | Cytidine Deaminase | Cytosine | DNA Methylation | Embryonic Development | Female | Gene Expression Regulation, Developmental | Gene Knock-In Techniques | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Nuclear Proteins | Promoter Regions, Genetic | Thymine DNA Glycosylase | Transcription, Genetic

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Associated grants

  • Agency: NCI NIH HHS, Id: CA06927
  • Agency: NCI NIH HHS, Id: CA78412
  • Agency: NIDDK NIH HHS, Id: DK067558
  • Agency: NCI NIH HHS, Id: P30 CA006927
  • Agency: NCI NIH HHS, Id: P30 CA006927-47
  • Agency: NCI NIH HHS, Id: R01 CA078412
  • Agency: NCI NIH HHS, Id: R01 CA078412-06
  • Agency: NCI NIH HHS, Id: R01 CA078412-07
  • Agency: NCI NIH HHS, Id: R01 CA078412-08
  • Agency: NCI NIH HHS, Id: R01 CA078412-09
  • Agency: NCI NIH HHS, Id: R01 CA078412-10
  • Agency: NCI NIH HHS, Id: R01 CA078412-11A2
  • Agency: NCI NIH HHS, Id: R01 CA078412-12
  • Agency: NCI NIH HHS, Id: R01 CA078412-13
  • Agency: NIGMS NIH HHS, Id: T32GM008216

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