Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

Gao, Linfeng, Emperle, Max, Guo, Yiran, Grimm, Sara A., Ren, Wendan, Adam, Sabrina, Uryu, Hidetaka, Zhang, Zhi-Min, Chen, Dongliang, Yin, Jiekai, Dukatz, Michael, Anteneh, Hiwot, Jurkowska, Renata Z. ORCID: https://orcid.org/0000-0002-4507-2222, Lu, Jiuwei, Wang, Yinsheng, Bashtrykov, Pavel, Wade, Paul A., Wang, Gang Greg, Jeltsch, Albert and Song, Jkui 2020. Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms. Nature Communications 11 , 3355. 10.1038/s41467-020-17109-4

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Abstract

Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substraterecognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals crucial and distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	1 June 2020
Date of Acceptance:	18 February 2020
Last Modified:	04 May 2023 03:27
URI:	https://orca.cardiff.ac.uk/id/eprint/132087

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