Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation Journal Article
| Authors: | Song, J.; Rechkoblit, O.; Bestor, T. H.; Patel, D. J. |
| Article Title: | Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation |
| Abstract: | Maintenance of genomic methylation patterns ismediated primarily by DNAmethyltransferase-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. |
| Keywords: | gene mutation; nonhuman; protein domain; animals; mice; complex formation; protein binding; enzyme activity; dna methylation; dna; amino acid sequence; molecular sequence data; cpg oligodeoxynucleotide; substrate specificity; genetic stability; dna structure; models, molecular; crystallography, x-ray; protein structure, tertiary; rodent; molecular interaction; mutant proteins; nucleic acid conformation; protein folding; gene insertion; catalytic domain; protein structure, secondary; dna methyltransferase 1; dna (cytosine-5-)-methyltransferase; cysteine; enzyme active site; inhibition; chemical binding; dinucleoside phosphates; dna-cytosine methylases |
| Journal Title: | Science |
| Volume: | 331 |
| Issue: | 6020 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2011-02-25 |
| Start Page: | 1036 |
| End Page: | 1040 |
| Language: | English |
| DOI: | 10.1126/science.1195380 |
| PUBMED: | 21163962 |
| PROVIDER: | scopus |
| PMCID: | PMC4689315 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 23 June 2011" - "CODEN: SCIEA" - "Source: Scopus" |
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