Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase

Monique G. P. van der Wijst, Muralidhar Venkiteswaran, Hui Chen, Guo-Liang Xu, Torsten Plosch, Marianne G. Rots*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

47 Citations (Scopus)

Abstract

Insights on active DNA demethylation disproved the original assumption that DNA methylation is a stable epigenetic modification. Interestingly, mammalian DNA methyltransferases 3A and 3B (DNMT-3A and -3B) have also been reported to induce active DNA demethylation, in addition to their well-known function in catalyzing methylation. In situations of extremely low levels of S-adenosyl methionine (SAM), DNMT-3A and -3B might demethylate C-5 methyl cytosine (5mC) via deamination to thymine, which is subsequently replaced by an unmodified cytosine through the base excision repair (BER) pathway. Alternatively, 5mC when converted to 5- hydroxymethylcytosine (5hmC) by TET enzymes, might be further modified to an unmodified cytosine by DNMT-3A and -3B under oxidized redox conditions, although exact pathways are yet to be elucidated. Interestingly, even direct conversion of 5mC to cytosine might be catalyzed by DNMTs. Here, we summarize the evidence on the DNA dehydroxymethylase and demethylase activity of DNMT-3A and -3B. Although physiological relevance needs to be demonstrated, the current indications on the 5mC- and 5hmC-modifying activities of de novo DNA C-5 methyltransferases shed a new light on these enzymes. Despite the extreme circumstances required for such unexpected reactions to occur, we here put forward that the chromatin microenvironment can be locally exposed to extreme conditions, and hypothesize that such waves of extremes allow enzymes to act in differential ways.

Original languageEnglish
Pages (from-to)671-676
Number of pages6
JournalEpigenetics
Volume10
Issue number8
DOIs
Publication statusPublished - 3-Aug-2015

Keywords

  • chromatin microenvironment
  • DNA dehydroxymethylation
  • DNA demethylation
  • DNMTs
  • oxidizing redox state
  • S-adenosyl methionine (SAM)
  • MAMMALIAN DNA
  • INDUCED TRANSCRIPTION
  • HISTONE DEMETHYLASE
  • MEMORY DEFICITS
  • GENE-EXPRESSION
  • TET PROTEINS
  • THYMINE DNA
  • METHYLATION
  • 5-METHYLCYTOSINE
  • LSD1

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