Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair
| Autor: | Lionel Larue, Florian Rambow, Marisa S. Bartolomei, Tiziana Bruno, Dominique Kobi, Salvatore Cortellino, Christophe Alberti, Alfonso Bellacosa, Irwin Davidson, Jinfei Xu, Yoshihiro Matsumoto, Antonio Cigliano, Mara Sannai, Maurizio Fanciulli, Lara K. Abramowitz, Andy Wessels, Dianne Robert Soprano, Karthik Devarajan, Andres J. Klein-Szanto, Elena Caretti, Madeleine Le Coz, Catherine Renner, Robert Moore, Maria Rosaria Bassi |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Transcription Genetic Deamination Embryonic Development Cell Cycle Proteins Biology Article General Biochemistry Genetics and Molecular Biology MBD4 Cytosine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cytidine Deaminase Animals Gene Knock-In Techniques Promoter Regions Genetic 030304 developmental biology Mice Knockout 0303 health sciences Biochemistry Genetics and Molecular Biology(all) Gene Expression Regulation Developmental Nuclear Proteins DNA Methylation Molecular biology Thymine DNA Glycosylase 3. Good health Mice Inbred C57BL 5-Methylcytosine DNA demethylation chemistry DNA glycosylase 030220 oncology & carcinogenesis DNA methylation Female Thymine-DNA glycosylase Nucleotide excision repair |
| Zdroj: | Cell. 146:67-79 |
| ISSN: | 0092-8674 |
| Popis: | SummaryDNA 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|