DNA Demethylation


Steady‐state levels of deoxyribonucleic acid (DNA) methylation result from a balance of two opposing biological forces: deposition of methyl groups by DNA methyltransferases and their removal by DNA demethylases. The removal of methyl groups from cytosine residues in DNA is an essential biological process that occurs at multiple points during development, differentiation and adult life in both plants and mammals. Demethylation can occur through passive dilution or through active enzymatic processes. Much progress has been made in recent years in the identification of enzymes responsible for active demethylation events. Higher plants have 5‐methylcytosine glycosylases that excise methylated cytosine. Mammals appear to rely on modification of 5‐methylcytosine through deamination or oxidation reactions that predispose the resulting base to repair pathways that result in replacement of 5‐methylcytosine with cytosine. The candidate demethylase enzymes in mammals are subject to translocation and inhibition in cancer, underscoring the biological importance of this process.

Key Concepts

  • Cytosine methylation is essential for mammalian life; demethylation of 5‐methylcytosine is likely to also be essential.
  • Demethylation of 5‐methylcytosine could occur through either a passive mechanism involving dilution through rounds of DNA replication or through an active, enzyme‐catalysed process.
  • Deamination of 5‐methylcytosine by APOBEC family enzymes in the context of DNA results in creation of thymine and a G:T mismatch, a substrate for conventional DNA repair machinery.
  • TET family enzymes progressively oxidise cytosine residues in DNA to forms that are recognised and excised by well‐characterised DNA glycosylases.
  • Enzymes identified as candidates in DNA demethylation are frequently mutated or translocated in cancer, suggesting that their precise spatial and temporal regulation is critical to mammalian cells.

Keywords: DNA methylation; DNA demethylation; TET ; APOBEC ; glycosylase

Figure 1. Cytosine methylation by DNA methyltransferases. The figure depicts the chemical structures of cytosine and 5‐methylcytosine. DNA methyltransferases catalyse the addition of methyl groups at carbon 5 of the pyrimidine ring.
Figure 2. APOBEC enzymes catalyse deamination of cytosine and cytosine derivatives. The figure depicts the chemical structures of pyrimidine bases utilised or produced by APOBEC action. In all cases, enzymatic activity results in deamination at the position 4 of the ring.
Figure 3. TET family enzymes oxidise cytosine. (a) The substrates and reaction products of TET‐dependent progressive oxidation of cytosine are shown. (b) Details of the reaction mechanism converting 5‐methylcytosine to 5‐hydroxymethylcytosine by TET enzymes are depicted. The enzymes utilise Fe(II) and α‐ketoglutarate as cofactors to activate an oxygen molecule that subsequently attacks a carbon–hydrogen bond on the methyl group of 5‐methyl C. The reaction generates carbon dioxide, succinate and 5‐hmC.


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Further Reading

Cheng X and Richards RJ (2014) Base flipping. Encyclopedia of Life Sciences. DOI: 10.1002/9780470015902.a0002714.pub3.

Guo F , Li X , Liang D , et al. (2014) Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15: 447–458.

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Rutledge CE , Murdock DJL and Walsh CP (2010) DNA methylation in development. Encyclopedia of Life Sciences. DOI: 10.1002/9780470015902.a0006155.pub2.

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Wade, Paul A(Mar 2015) DNA Demethylation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006161.pub2]