title: Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation.
abstract: Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1). We have solved structures of mouse and human DNMT1 composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation. In addition, a loop projecting from BAH2 interacts with the target recognition domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted position and preventing it from inserting into the DNA major groove. Our studies identify an autoinhibitory mechanism, in which unmethylated CpG dinucleotides are occluded from the active site to ensure that only hemimethylated CpG dinucleotides undergo methylation.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jikui
authors.initials: J
authors.lastname: Song
authors.forename: Olga
authors.initials: O
authors.lastname: Rechkoblit
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Bestor
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003545:Cysteine; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry* / Q000378:metabolism*; D019175:DNA Methylation; D015257:DNA-Cytosine Methylases / Q000737:chemistry / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D003545:Cysteine; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D015257:DNA-Cytosine Methylases; D015226:Dinucleoside Phosphates; D050505:Mutant Proteins; C015772:CpG dinucleotide; C037664:DNA modification methylase HhaI; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse