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Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

Author

Listed:
  • Kosuke Yamaguchi

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

  • Xiaoying Chen

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

  • Brianna Rodgers

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

  • Fumihito Miura

    (Kyushu University Graduate School of Medical Sciences)

  • Pavel Bashtrykov

    (University of Stuttgart)

  • Frédéric Bonhomme

    (Chem4Life)

  • Catalina Salinas-Luypaert

    (CNRS, UMR 144)

  • Deis Haxholli

    (Ludwig-Maximilians-Universität München)

  • Nicole Gutekunst

    (University of Stuttgart)

  • Bihter Özdemir Aygenli

    (Helmholtz Zentrum München)

  • Laure Ferry

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

  • Olivier Kirsh

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

  • Marthe Laisné

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

  • Andrea Scelfo

    (CNRS, UMR 144)

  • Enes Ugur

    (Ludwig-Maximilians-Universität München)

  • Paola B. Arimondo

    (Chem4Life)

  • Heinrich Leonhardt

    (Ludwig-Maximilians-Universität München)

  • Masato T. Kanemaki

    (National Institute of Genetics, Research Organization of Information and Systems (ROIS)
    SOKENDAI
    The University of Tokyo)

  • Till Bartke

    (Helmholtz Zentrum München)

  • Daniele Fachinetti

    (CNRS, UMR 144)

  • Albert Jeltsch

    (University of Stuttgart)

  • Takashi Ito

    (Kyushu University Graduate School of Medical Sciences)

  • Pierre-Antoine Defossez

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

Abstract

DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47314-4
    DOI: 10.1038/s41467-024-47314-4
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