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

Linfeng Gao, Max Emperle, Yiran Guo, Sara A. Grimm, Wendan Ren, Sabrina Adam, Hidetaka Uryu, Zhi-Min Zhang, Dongliang Chen, Jiekai Yin, Michael Dukatz, Hiwot Anteneh, Renata Z. Jurkowska, Jiuwei Lu, Yinsheng Wang, Pavel Bashtrykov, Paul A. Wade, Gang Greg Wang (), Albert Jeltsch () and Jikui Song ()
Additional contact information
Linfeng Gao: University of California
Max Emperle: University of Stuttgart
Yiran Guo: University of North Carolina at Chapel Hill School of Medicine
Sara A. Grimm: National Institute of Environmental Health Sciences
Wendan Ren: University of California
Sabrina Adam: University of Stuttgart
Hidetaka Uryu: University of North Carolina at Chapel Hill School of Medicine
Zhi-Min Zhang: University of California
Dongliang Chen: University of North Carolina at Chapel Hill School of Medicine
Jiekai Yin: University of California
Michael Dukatz: University of Stuttgart
Hiwot Anteneh: University of California
Renata Z. Jurkowska: University of Stuttgart
Jiuwei Lu: University of California
Yinsheng Wang: University of California
Pavel Bashtrykov: University of Stuttgart
Paul A. Wade: National Institute of Environmental Health Sciences
Gang Greg Wang: University of North Carolina at Chapel Hill School of Medicine
Albert Jeltsch: University of Stuttgart
Jikui Song: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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 substrate-recognition 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 distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.

Date: 2020
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DOI: 10.1038/s41467-020-17109-4

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