Structural basis for DNMT3A-mediated de novo DNA methylation

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

doi:10.1038/nature25477

Title: Structural basis for DNMT3A-mediated de novo DNA methylation

Journal Article · Wed Feb 07 00:00:00 EST 2018 · Nature (London)

DOI:https://doi.org/10.1038/nature25477· OSTI ID:1433691

Zhang, Zhi-Min ^[1]; Lu, Rui ^[2]; Wang, Pengcheng ^[3]; Yu, Yang ^[3]; Chen, Dongliang ^[2]; Gao, Linfeng ^[3]; Liu, Shuo ^[3]; Ji, Debin ^[3]; Rothbart, Scott B. ^[4]; Wang, Yinsheng ^[3]; Wang, Gang Greg ^[2]; Song, Jikui ^[3]

Jinan Univ., Guangzhou (China); Univ. of California, Riverside, CA (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)
Univ. of California, Riverside, CA (United States)
Univ. of North Carolina, Chapel Hill, NC (United States); Van Andel Research Inst., Grand Rapids, MI (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); UNC Cancer Center Core Support; Gabrielle’s Angel Foundation for Cancer Research; Univ. Cancer Research Fund of the N.C. state; National Inst. of Health

Grant/Contract Number:: P30-CA016086; 1R35GM119721; R35GM124736; 5R21ES025392; 1R01CA215284; 1R01CA218600; 1R01CA211336

OSTI ID:: 1433691

Journal Information:: Nature (London), Vol. 554, Issue 7692; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 142 works

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