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Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation

Author

Listed:
  • Atsuya Nishiyama

    (The University of Tokyo)

  • Christopher B. Mulholland

    (Ludwig-Maximilians-Universität München)

  • Sebastian Bultmann

    (Ludwig-Maximilians-Universität München)

  • Satomi Kori

    (Yokohama City University)

  • Akinori Endo

    (Tokyo Metropolitan Institute of Medical Science)

  • Yasushi Saeki

    (Tokyo Metropolitan Institute of Medical Science)

  • Weihua Qin

    (Ludwig-Maximilians-Universität München)

  • Carina Trummer

    (Ludwig-Maximilians-Universität München)

  • Yoshie Chiba

    (The University of Tokyo)

  • Haruka Yokoyama

    (Yokohama City University)

  • Soichiro Kumamoto

    (The University of Tokyo)

  • Toru Kawakami

    (Osaka University)

  • Hironobu Hojo

    (Osaka University)

  • Genta Nagae

    (University of Tokyo)

  • Hiroyuki Aburatani

    (University of Tokyo)

  • Keiji Tanaka

    (Tokyo Metropolitan Institute of Medical Science)

  • Kyohei Arita

    (Yokohama City University)

  • Heinrich Leonhardt

    (Ludwig-Maximilians-Universität München)

  • Makoto Nakanishi

    (The University of Tokyo)

Abstract

Stable inheritance of DNA methylation is critical for maintaining differentiated phenotypes in multicellular organisms. We have recently identified dual mono-ubiquitylation of histone H3 (H3Ub2) by UHRF1 as an essential mechanism to recruit DNMT1 to chromatin. Here, we show that PCNA-associated factor 15 (PAF15) undergoes UHRF1-dependent dual mono-ubiquitylation (PAF15Ub2) on chromatin in a DNA replication-coupled manner. This event will, in turn, recruit DNMT1. During early S-phase, UHRF1 preferentially ubiquitylates PAF15, whereas H3Ub2 predominates during late S-phase. H3Ub2 is enhanced under PAF15 compromised conditions, suggesting that H3Ub2 serves as a backup for PAF15Ub2. In mouse ES cells, loss of PAF15Ub2 results in DNA hypomethylation at early replicating domains. Together, our results suggest that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are prerequisite for high fidelity DNA methylation inheritance.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15006-4
    DOI: 10.1038/s41467-020-15006-4
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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. 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.
    3. 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.

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