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Structural basis for DNMT3A-mediated de novo DNA methylation
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Structural basis for DNMT3A-mediated de novo DNA methylation
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Journal Article
Structural basis for DNMT3A-mediated de novo DNA methylation
2018
Overview
A crystal structure of DNMT3A and its regulatory partner DNMT3L bound to DNA reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.
Structure of the DNA methylation mediator DNMT3A
Methylation of DNA at CG dinucleotides is an important epigenetic regulatory event. It is associated with processes such as silencing of gene transcription, genomic imprinting and cell fate determination. DNA methylation is established by the
de novo
DNA methyltransferases DNMT3A and DNMT3B and is subsequently maintained by DNMT1. Here, Jikui Song and colleagues have determined a crystal structure of DNMT3A and its regulatory partner DNMT3L bound to DNA, revealing how the CG dinucleotide is specifically recognized by a DNMT3A–DNMT3L tetramer. They also analyse the effect of cancer-associated mutations in DNMT3A, showing that the DNA-binding residues of DNMT3A are crucial to establishing appropriate cellular DNA methylation patterns and are associated with deregulated proliferation.
DNA methylation by
de novo
DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development
1
,
2
. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A–DNMT3L–DNA complex in which two DNMT3A monomers simultaneously attack two cytosine–phosphate–guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A–DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
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/ 45
/ 45/15
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/ 45/23
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/ 45/70
/ 45/77
/ 82/16
/ 82/29
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/ Cancer
/ Cytosine
/ DNA
/ DNA (Cytosine-5-)-Methyltransferases - chemistry
/ DNA (Cytosine-5-)-Methyltransferases - genetics
/ DNA (Cytosine-5-)-Methyltransferases - metabolism
/ DNA-Binding Proteins - chemistry
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Genomes
/ Guanine
/ Hematologic Neoplasms - enzymology
/ Hematologic Neoplasms - genetics
/ Hematologic Neoplasms - pathology
/ Humanities and Social Sciences
/ Humans
/ letter
/ Leukemia
/ Monomers
/ Mutation
/ Proteins
/ Science
