Research Article

Structure of DNMT1-DNA Complex Reveals a Role for Autoinhibition in Maintenance DNA Methylation

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Science  16 Dec 2010:
DOI: 10.1126/science.1195380


Maintenance of genomic methylation patterns is mediated primarily by DNA methyltransferase-1 (DNMT1). We have solved structures of mouse 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, thereby 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, whereby occlusion of unmethylated CpG dinucleotides from de novo methylation ensures that only hemimethylated CpG dinucleotides gain access to the active site.