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

Salvatore Cortellino, Jinfei Xu, Mara Sannai, Robert Moore, Elena Caretti, Antonio Cigliano, Madeleine Le Coz, Karthik Devarajan, Andy Wessels, Dianne Soprano, Lara K. Abramowitz, Marisa S. Bartolomei, Florian Rambow, Maria Rosaria Bassi, Tiziana Bruno, Maurizio Fanciulli, Catherine Renner, Andres J. Klein-Szanto, Yoshihiro Matsumoto, Dominique KobiIrwin Davidson, Christophe Alberti, Lionel Larue, Alfonso Bellacosa

Research output: Contribution to journalArticlepeer-review

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. PaperClip:

Original languageEnglish
Pages (from-to)67-79
Number of pages13
JournalCell
Volume146
Issue number1
DOIs
Publication statusPublished - Jul 8 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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