IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34779-4.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34779-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34779-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Atsuya Nishiyama & Christopher B. Mulholland & Sebastian Bultmann & Satomi Kori & Akinori Endo & Yasushi Saeki & Weihua Qin & Carina Trummer & Yoshie Chiba & Haruka Yokoyama & Soichiro Kumamoto & Toru, 2020. "Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Robert P. Rambo & John A. Tainer, 2013. "Accurate assessment of mass, models and resolution by small-angle scattering," Nature, Nature, vol. 496(7446), pages 477-481, April.
    3. 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.
    4. Jafar Sharif & Masahiro Muto & Shin-ichiro Takebayashi & Isao Suetake & Akihiro Iwamatsu & Takaho A. Endo & Jun Shinga & Yoko Mizutani-Koseki & Tetsuro Toyoda & Kunihiro Okamura & Shoji Tajima & Kohzo, 2007. "The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA," Nature, Nature, vol. 450(7171), pages 908-912, December.
    5. Atsuya Nishiyama & Luna Yamaguchi & Jafar Sharif & Yoshikazu Johmura & Takeshi Kawamura & Keiko Nakanishi & Shintaro Shimamura & Kyohei Arita & Tatsuhiko Kodama & Fuyuki Ishikawa & Haruhiko Koseki & M, 2013. "Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication," Nature, Nature, vol. 502(7470), pages 249-253, October.
    6. Zhi-Min Zhang & Rui Lu & Pengcheng Wang & Yang Yu & Dongliang Chen & Linfeng Gao & Shuo Liu & Debin Ji & Scott B Rothbart & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2018. "Structural basis for DNMT3A-mediated de novo DNA methylation," Nature, Nature, vol. 554(7692), pages 387-391, February.
    7. George V. Avvakumov & John R. Walker & Sheng Xue & Yanjun Li & Shili Duan & Christian Bronner & Cheryl H. Arrowsmith & Sirano Dhe-Paganon, 2008. "Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1," Nature, Nature, vol. 455(7214), pages 822-825, October.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. 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.
    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. 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.
    4. 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.
    5. Johnny Lisboa & Cassilda Pereira & Rute D. Pinto & Inês S. Rodrigues & Liliana M. G. Pereira & Bruno Pinheiro & Pedro Oliveira & Pedro José Barbosa Pereira & Jorge E. Azevedo & Dominique Durand & Rola, 2023. "Unconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. María Arroyo & Florian D. Hastert & Andreas Zhadan & Florian Schelter & Susanne Zimbelmann & Cathia Rausch & Anne K. Ludwig & Thomas Carell & M. Cristina Cardoso, 2022. "Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation," Nature Communications, Nature, vol. 13(1), pages 1-28, December.
    7. Xiang Chen & Yan Wang & Zhonghe Xu & Meng-Li Cheng & Qing-Qing Ma & Rui-Ting Li & Zheng-Jian Wang & Hui Zhao & Xiaobing Zuo & Xiao-Feng Li & Xianyang Fang & Cheng-Feng Qin, 2023. "Zika virus RNA structure controls its unique neurotropism by bipartite binding to Musashi-1," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Steffen Mueller & Gail Dennison & Shujun Liu, 2021. "An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality," IJERPH, MDPI, vol. 18(13), pages 1-23, June.
    9. Re’em Moskovitz & Tossapol Pholcharee & Sophia M. DonVito & Bora Guloglu & Edward Lowe & Franziska Mohring & Robert W. Moon & Matthew K. Higgins, 2023. "Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    10. 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.
    11. Jan Felix & Ladislav Bumba & Clarissa Liesche & Angélique Fraudeau & Fabrice Rébeillé & Jessica Y. El Khoury & Karine Huard & Benoit Gallet & Christine Moriscot & Jean-Philippe Kleman & Yoan Duhoo & M, 2022. "The AAA+ ATPase RavA and its binding partner ViaA modulate E. coli aminoglycoside sensitivity through interaction with the inner membrane," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    12. Jienyu Ding & Yun-Tzai Lee & Yuba Bhandari & Charles D. Schwieters & Lixin Fan & Ping Yu & Sergey G. Tarosov & Jason R. Stagno & Buyong Ma & Ruth Nussinov & Alan Rein & Jinwei Zhang & Yun-Xing Wang, 2023. "Visualizing RNA conformational and architectural heterogeneity in solution," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Clara Cousu & Eléonore Mulot & Annie Smet & Sara Formichetti & Damiana Lecoeuche & Jianke Ren & Kathrin Muegge & Matthieu Boulard & Jean-Claude Weill & Claude-Agnès Reynaud & Sébastien Storck, 2023. "Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    14. Zheng Zhao & Liang Li & Ruichen Zeng & Liangguan Lin & Dongwei Yuan & Yejie Wen & Na Li & Yingying Cui & Shiming Zhu & Zhi-Min Zhang & Sheng Li & Chonghua Ren, 2023. "5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34779-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.