Active DNA demethylation by Gadd45 and DNA repair.pdf

Active DNA demethylation by Gadd45 and DNA repair Christof Niehrs1,2 and Andrea Scha? fer1 1 Institute of Molecular Biology, 55128 Mainz, Germany 2 Division of Molecular Embryology, German Cancer Research Center (DKFZ)–Center for Molecular Biology of the University of Heidelberg (ZMBH) Alliance, 69120 Heidelberg, Germany ReviewHow DNA methylation patterns are established, main- tained and remodeled is incompletely understood, how- ever, it has become clear that DNA methylation is reversible and dynamic as a result of enzymatic DNA demethylation. Several different mechanisms that may account for demethylation have recently been put for- ward and all seem to involve DNA repair. Here, we review DNA demethylation mediated by multifunctional growth arrest and DNA damage 45 (Gadd45) protein family members which mediate DNA demethylation during cell differentiation and stress response. Gadd45 recruits nucleotide and/or base excision repair factors to gene-specific loci and acts as an adapter between repair factors and chromatin, thereby creating a nexus be- tween epigenetics and DNA repair. Dynamics of DNA methylation DNA methylation is a common epigenetic mark conserved in many eukaryotes including protists, fungi, plants and ani- mals. Eukaryotic DNA methylation is primarily confined to cytosine bases and is associated with transcriptional silenc- ing. In animals, DNA methylation predominantly occurs at CpG dinucleotides, but in embryonic stem cells it is also found in non-CpG contexts [1–3]. In many promoters the presence of 5-methylcytosine (5mC) promotes gene silenc- ing, and hence DNA methylation is implicated in imprint- ing, X chromosome inactivation, embryonic development, tissue-specific gene expression, and cancer (reviewed in [4– 6]). More recently, oxidized derivatives of 5mC, including 5- hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcy- tosine, have been recognized in a variety of mammalian cells [7–11]. Methylation patterns are mitotically and meiot