title: Crystal Structure of Human DNA Methyltransferase 1.
abstract: DNMT1 (DNA methyltransferase 1) is responsible for propagating the DNA methylation patterns during DNA replication. DNMT1 contains, in addition to a C-terminal methyltransferase domain, a large N-terminal regulatory region that is composed of an RFTS (replication foci targeting sequence) domain, a CXXC zinc finger domain and a pair of BAH (bromo adjacent homology) domains. The regulatory domains of DNMT1 mediate a network of protein-protein and protein-DNA interactions to control the recruitment and enzymatic activity of DNMT1. Here we report the crystal structure of human DNMT1 with all the structural domains (hDNMT1, residues 351-1600) in complex with S-adenosyl-l-homocysteine at 2.62Å resolution. The RFTS domain directly associates with the methyltransferase domain, thereby inhibiting the substrate binding of hDNMT1. Through structural analysis, mutational, biochemical and enzymatic studies, we further identify that a linker sequence between the CXXC and BAH1 domains, aside from its role in the CXXC domain-mediated DNMT1 autoinhibition, serves as an important regulatory element in the RFTS domain-mediated autoinhibition. In comparison with the previously determined structure of mouse DNMT1, this study also reveals a number of distinct structural features that may underlie subtle functional diversity observed for the two orthologues. In addition, this structure provides a framework for understanding the functional consequence of disease-related hDNMT1 mutations.
authors.affiliation: Department of Biochemistry, University of California, Riverside, CA 92521, USA.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Zhang
authors.affiliation: Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521, USA; Department of Chemistry, University of California, Riverside, CA 92521, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, University of California, Riverside, CA 92521, USA.
authors.forename: Krystal
authors.initials: K
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Biochemistry, University of California, Riverside, CA 92521, USA.
authors.forename: John Jefferson
authors.initials: JJ
authors.lastname: Perry
authors.affiliation: Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521, USA; Department of Chemistry, University of California, Riverside, CA 92521, USA.
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of California, Riverside, CA 92521, USA. Electronic address: jikui.song@ucr.edu.
authors.forename: Jikui
authors.initials: J
authors.lastname: Song
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics; D018360:Crystallography, X-Ray; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse
keywords: DNA methylation; DNMT1; allosteric regulation; autoinhibition; epigenetics