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Nature
2015 Jan 29;5177536:640-4. doi: 10.1038/nature13899.
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Structural insight into autoinhibition and histone H3-induced activation of DNMT3A.
Guo X, Wang L, Li J, Ding Z, Xiao J, Yin X, He S, Shi P, Dong L, Li G, Tian C, Wang J, Cong Y, Xu Y.
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DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.
Adams,
PHENIX: building new software for automated crystallographic structure determination.
2002, Pubmed
Adams,
PHENIX: building new software for automated crystallographic structure determination.
2002,
Pubmed Bestor,
The DNA methyltransferases of mammals.
2000,
Pubmed Bird,
DNA methylation patterns and epigenetic memory.
2002,
Pubmed Bird,
Variable patterns of total DNA and rDNA methylation in animals.
1980,
Pubmed Cedar,
Linking DNA methylation and histone modification: patterns and paradigms.
2009,
Pubmed Chedin,
The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a.
2002,
Pubmed Chen,
A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation.
2002,
Pubmed Cong,
4.0-A resolution cryo-EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement.
2010,
Pubmed Cong,
Single particle analysis at high resolution.
2010,
Pubmed Ehrlich,
Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells.
1982,
Pubmed Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed Guibert,
Dynamic regulation of DNA methylation during mammalian development.
2009,
Pubmed Jaenisch,
Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.
2003,
Pubmed Jia,
Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation.
2007,
Pubmed Klimasauskas,
HhaI methyltransferase flips its target base out of the DNA helix.
1994,
Pubmed Laurent,
Dynamic changes in the human methylome during differentiation.
2010,
Pubmed Law,
Establishing, maintaining and modifying DNA methylation patterns in plants and animals.
2010,
Pubmed Li,
Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase.
2011,
Pubmed Lister,
Human DNA methylomes at base resolution show widespread epigenomic differences.
2009,
Pubmed Ludtke,
A 11.5 A single particle reconstruction of GroEL using EMAN.
2001,
Pubmed Ludtke,
EMAN: semiautomated software for high-resolution single-particle reconstructions.
1999,
Pubmed Luger,
Expression and purification of recombinant histones and nucleosome reconstitution.
1999,
Pubmed McCoy,
Phaser crystallographic software.
2007,
Pubmed Meissner,
Genome-scale DNA methylation maps of pluripotent and differentiated cells.
2008,
Pubmed Okano,
Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases.
1998,
Pubmed Okano,
DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.
1999,
Pubmed Ooi,
DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.
2007,
Pubmed Otani,
Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain.
2009,
Pubmed Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed Rajavelu,
Function and disruption of DNA methyltransferase 3a cooperative DNA binding and nucleoprotein filament formation.
2012,
Pubmed Roth,
Biotin-avidin microplate assay for the quantitative analysis of enzymatic methylation of DNA by DNA methyltransferases.
2000,
Pubmed Shi,
Site-specific ¹⁹F NMR chemical shift and side chain relaxation analysis of a membrane protein labeled with an unnatural amino acid.
2011,
Pubmed Shi,
Site-specific protein backbone and side-chain NMR chemical shift and relaxation analysis of human vinexin SH3 domain using a genetically encoded 15N/19F-labeled unnatural amino acid.
2010,
Pubmed Simon,
The site-specific installation of methyl-lysine analogs into recombinant histones.
2007,
Pubmed
,
Xenbase Smith,
DNA methylation: roles in mammalian development.
2013,
Pubmed Tang,
EMAN2: an extensible image processing suite for electron microscopy.
2007,
Pubmed van Heel,
A new generation of the IMAGIC image processing system.
1996,
Pubmed Weber,
Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.
2007,
Pubmed Zhang,
Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail.
2010,
Pubmed
,
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