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

Kosuke Yamaguchi (), Xiaoying Chen, Brianna Rodgers, Fumihito Miura, Pavel Bashtrykov, Frédéric Bonhomme, Catalina Salinas-Luypaert, Deis Haxholli, Nicole Gutekunst, Bihter Özdemir Aygenli, Laure Ferry, Olivier Kirsh, Marthe Laisné, Andrea Scelfo, Enes Ugur, Paola B. Arimondo, Heinrich Leonhardt, Masato T. Kanemaki, Till Bartke, Daniele Fachinetti, Albert Jeltsch, Takashi Ito and Pierre-Antoine Defossez ()
Additional contact information
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)
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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47314-4

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