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Structural Basis for DNMT3A-mediated De Novo DNA Methylation

Structural Basis for DNMT3A-mediated De Novo DNA Methylation

Zhi-Min Zhang, Rui Lu, Pengcheng Wang, Yang Yu, Dongliang Chen, Linfeng Gao, Shuo Liu, Debin Ji, Scott B Rothbart, Yinsheng Wang, Gang Greg Wang, Jikui Song

Nature. 2018 Feb 15;554(7692):387-391.

PMID: 29414941

Abstract:

DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413459	DNMT3A/DNMT3L active human			Price

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