title: Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain.
abstract: DNMT3 proteins are de novo DNA methyltransferases that are responsible for the establishment of DNA methylation patterns in mammalian genomes. Here, we have determined the crystal structures of the ATRX-DNMT3-DNMT3L (ADD) domain of DNMT3A in an unliganded form and in a complex with the amino-terminal tail of histone H3. Combined with the results of biochemical analysis, the complex structure indicates that DNMT3A recognizes the unmethylated state of lysine 4 in histone H3. This finding indicates that the recruitment of DNMT3A onto chromatin, and thereby de novo DNA methylation, is mediated by recognition of the histone modification state by its ADD domain. Furthermore, our biochemical and nuclear magnetic resonance data show mutually exclusive binding of the ADD domain of DNMT3A and the chromodomain of heterochromatin protein 1alpha to the H3 tail. These results indicate that de novo DNA methylation by DNMT3A requires the alteration of chromatin structure.
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Otani
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nankumo
authors.forename: Kyohei
authors.initials: K
authors.lastname: Arita
authors.forename: Susumu
authors.initials: S
authors.lastname: Inamoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Ariyoshi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shirakawa
mesh_terms: D002843:Chromatin / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry* / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006657:Histones / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D002843:Chromatin; C000717967:DNMT3A protein, human; D006657:Histones; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A