Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond - PubMed (original) (raw)

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Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond

Junjie U Guo et al. Cell Cycle. 2011.

Abstract

Cytosine methylation is the major epigenetic modification of metazoan DNA. Although there is strong evidence that active DNA demethylation occurs in animal cells, the molecular details of this process are unknown. The recent discovery of the TET protein family (TET1-3) 5-methylcytosine hydroxylases has provided a new entry point to reveal the identity of the long-sought DNA demethylase. Here, we review the recent progress in understanding the function of TET proteins and 5-hydroxymethylcytosine (5hmC) through various biochemical and genomic approaches, the current evidence for a role of 5hmC as an early intermediate in active DNA demethylation and the potential functions of TET proteins and 5hmC beyond active DNA demethylation. We also discuss how future studies can extend our knowledge of this novel epigenetic modification.

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Figures

Figure 1

Figure 1

Potential mechanisms for active DNA demethylation through 5hmC. (1) Evidence suggests that 5hmC may be converted to 5hmU by AID/APOBEC deaminases and repaired by the base excision repair (BER) pathway. (2) 5hmC may also be further oxidized to 5-carboxylcytosine and decarboxylated/repaired to C. (3) A 5hmC glycosylases may excise 5hmC and directly initiate BER. (4) Direct conversion from 5hmC to C may also occur. (5) Nuclear excision repair (NER) pathway may excise 5hmC-containing DNA strands. Besides promoting DNA demethylation, 5hmC may regulate transcription through unidentified 5hmC-binding proteins. Solid arrows indicate catalytic steps that are supported by experimental evidence, whereas dashed arrows indicate speculative processes.

Figure 2

Figure 2

Neuronal activity-induced DNA demethylation in the adult brain. Neuronal activation in the dentate gyrus induces expression of Gadd45b, which plays an essential role in demethylation of Bdnf and Fgf1 promoters. This process also involves Tet1 and Apobec1. Gadd45b-dependent DNA demethylation leads to expression of important genes, such as Bdnf and Fgf1, and can potentially have a broad impact in the mature nervous system.

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