Review

TET enzymes, TDG and the dynamics of DNA demethylation

  • Nature volume 502, pages 472479 (24 October 2013)
  • doi:10.1038/nature12750
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Abstract

DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.

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Acknowledgements

We would like to thank S. Yamaguchi for preparing Figure 3; D. Crawford, A. Inoue, C. Nabel, E. Schutsky and S. Yamaguchi for their helpful comments. We apologize to the people whose work cannot be cited due to space limitations. Our DNA methylation-related work is supported by the NIH (U01DK089565 and GM068804 to Y.Z., and K08-AI089242 to R.M.K.), the Rita Allen Foundation (R.M.K.) and HHMI (Y.Z.). Y.Z. is an investigator of the HHMI.

Author information

Affiliations

  1. Department of Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.

    • Rahul M. Kohli
  2. Department of Biochemistry and Biophysics, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA.

    • Rahul M. Kohli
  3. Howard Hughes Medical Institute, WAB-1496, 200 Longwood Ave., Boston, Massachusetts 02115, USA.

    • Yi Zhang
  4. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

    • Yi Zhang
  5. Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts 02115, USA

    • Yi Zhang
  6. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Yi Zhang
  7. Harvard Stem Cell Institute, 200 Longwood Ave., Boston, Massachusetts 02115, USA.

    • Yi Zhang

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Rahul M. Kohli or Yi Zhang.

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