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

Author

Listed:
  • Linfeng Gao

    (University of California)

  • Max Emperle

    (University of Stuttgart)

  • Yiran Guo

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill)

  • 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
    Jinan University)

  • Dongliang Chen

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill)

  • Jiekai Yin

    (University of California)

  • Michael Dukatz

    (University of Stuttgart)

  • Hiwot Anteneh

    (University of California)

  • Renata Z. Jurkowska

    (University of Stuttgart
    Cardiff University)

  • Jiuwei Lu

    (University of California)

  • Yinsheng Wang

    (University of California
    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
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Albert Jeltsch

    (University of Stuttgart)

  • Jikui Song

    (University of California
    University of California)

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.

Suggested Citation

  • 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 &, 2020. "Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17109-4
    DOI: 10.1038/s41467-020-17109-4
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    Cited by:

    1. Amika Kikuchi & Hiroki Onoda & Kosuke Yamaguchi & Satomi Kori & Shun Matsuzawa & Yoshie Chiba & Shota Tanimoto & Sae Yoshimi & Hiroki Sato & Atsushi Yamagata & Mikako Shirouzu & Naruhiko Adachi & Jafa, 2022. "Structural basis for activation of DNMT1," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Linfeng Gao & Yiran Guo & Mahamaya Biswal & Jiuwei Lu & Jiekai Yin & Jian Fang & Xinyi Chen & Zengyu Shao & Mengjiang Huang & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2022. "Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. André Bortolini Silveira & Alexandre Houy & Olivier Ganier & Begüm Özemek & Sandra Vanhuele & Anne Vincent-Salomon & Nathalie Cassoux & Pascale Mariani & Gaelle Pierron & Serge Leyvraz & Damian Rieke , 2024. "Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Jian Fang & Jianjun Jiang & Sarah M. Leichter & Jie Liu & Mahamaya Biswal & Nelli Khudaverdyan & Xuehua Zhong & Jikui Song, 2022. "Mechanistic basis for maintenance of CHG DNA methylation in plants," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Jiuwei Lu & Yiran Guo & Jiekai Yin & Jianbin Chen & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2024. "Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Kosuke Yamaguchi & Xiaoying Chen & Brianna Rodgers & Fumihito Miura & Pavel Bashtrykov & Frédéric Bonhomme & Catalina Salinas-Luypaert & Deis Haxholli & Nicole Gutekunst & Bihter Özdemir Aygenli & Lau, 2024. "Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Xinyi Chen & Yiran Guo & Ting Zhao & Jiuwei Lu & Jian Fang & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2024. "Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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