The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases.
For cytosine (C) demethylation of vertebrate DNA, it is known that the TET proteins could convert 5-methyl C (5-mC) to 5-hydroxymethyl C (5-hmC). However, DNA dehydroxymethylase(s), or enzymes able to directly convert 5-hmC to C, have been elusive. We present in vitro evidence that the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B, but not the maintenance enzyme DNMT1, are also redox-dependent DNA dehydroxymethylases. Significantly, intactness of the C methylation catalytic sites of these de novo enzymes is also required for their 5-hmC dehydroxymethylation activity. That DNMT3A and DNMT3B function bidirectionally both as DNA methyltransferases and as dehydroxymethylases raises intriguing and new questions regarding the structural and functional aspects of these enzymes and their regulatory roles in the dynamic modifications of the vertebrate genomes during development, carcinogenesis, and gene regulation.
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 115, Taiwan.
Chun-Chang
CC
Chen
Keh-Yang
KY
Wang
Che-Kun James
CK
Shen
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002855:Chromatography, Thin Layer / Q000379:methods; D004247:DNA / Q000737:chemistry; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases / Q000737:chemistry / Q000502:physiology*; D049308:Dioxygenases / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction; D010957:Plasmids / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases; D049308:Dioxygenases; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse