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Structural basis for activation of DNMT1

Author

Listed:
  • Amika Kikuchi

    (Yokohama City University, Tsurumi-ku)

  • Hiroki Onoda

    (Yokohama City University, Tsurumi-ku
    Nagoya University, Furo-Cho)

  • Kosuke Yamaguchi

    (Université Paris Cité, CNRS, Epigenetics and Cell Fate)

  • Satomi Kori

    (Yokohama City University, Tsurumi-ku)

  • Shun Matsuzawa

    (Yokohama City University, Tsurumi-ku)

  • Yoshie Chiba

    (The University of Tokyo)

  • Shota Tanimoto

    (The University of Tokyo)

  • Sae Yoshimi

    (Yokohama City University, Tsurumi-ku)

  • Hiroki Sato

    (Yokohama City University, Tsurumi-ku)

  • Atsushi Yamagata

    (RIKEN Center for Biosystems Dynamics Research)

  • Mikako Shirouzu

    (RIKEN Center for Biosystems Dynamics Research)

  • Naruhiko Adachi

    (High Energy Accelerator Research Organization (KEK))

  • Jafar Sharif

    (RIKEN Center for Integrative Medical Sciences (IMS))

  • Haruhiko Koseki

    (RIKEN Center for Integrative Medical Sciences (IMS)
    Chiba University)

  • Atsuya Nishiyama

    (The University of Tokyo)

  • Makoto Nakanishi

    (The University of Tokyo)

  • Pierre-Antoine Defossez

    (Université Paris Cité, CNRS, Epigenetics and Cell Fate)

  • Kyohei Arita

    (Yokohama City University, Tsurumi-ku)

Abstract

DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial “Toggle” pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34779-4
    DOI: 10.1038/s41467-022-34779-4
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    1. 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.
    2. 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.

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