title: Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair.
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.
authors: Cancer Biology Program and Epigenetics and Progenitor Cells Keystone Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Salvatore
authors: S
authors: Cortellino
authors: Jinfei
authors: J
authors: Xu
authors: Mara
authors: M
authors: Sannai
authors: Robert
authors: R
authors: Moore
authors: Elena
authors: E
authors: Caretti
authors: Antonio
authors: A
authors: Cigliano
authors: Madeleine
authors: M
authors: Le Coz
authors: Karthik
authors: K
authors: Devarajan
authors: Andy
authors: A
authors: Wessels
authors: Dianne
authors: D
authors: Soprano
authors: Lara K
authors: LK
authors: Abramowitz
authors: Marisa S
authors: MS
authors: Bartolomei
authors: Florian
authors: F
authors: Rambow
authors: Maria Rosaria
authors: MR
authors: Bassi
authors: Tiziana
authors: T
authors: Bruno
authors: Maurizio
authors: M
authors: Fanciulli
authors: Catherine
authors: C
authors: Renner
authors: Andres J
authors: AJ
authors: Klein-Szanto
authors: Yoshihiro
authors: Y
authors: Matsumoto
authors: Dominique
authors: D
authors: Kobi
authors: Irwin
authors: I
authors: Davidson
authors: Christophe
authors: C
authors: Alberti
authors: Lionel
authors: L
authors: Larue
authors: Alfonso
authors: A
authors: Bellacosa
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D044502:Thymine DNA Glycosylase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000097642:GADD45 Proteins
chemical_list: D044503:5-Methylcytosine; D018797:Cell Cycle Proteins; D003564:Cytidine Deaminase; D003596:Cytosine; D009687:Nuclear Proteins; D044502:Thymine DNA Glycosylase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C011865:5-hydroxymethylcytosine