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

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 th...

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Veröffentlicht in:Nature communications 2024-04, Vol.15 (1), p.2960-2960, Article 2960
Hauptverfasser: Yamaguchi, Kosuke, Chen, Xiaoying, Rodgers, Brianna, Miura, Fumihito, Bashtrykov, Pavel, Bonhomme, Frédéric, Salinas-Luypaert, Catalina, Haxholli, Deis, Gutekunst, Nicole, Aygenli, Bihter Özdemir, Ferry, Laure, Kirsh, Olivier, Laisné, Marthe, Scelfo, Andrea, Ugur, Enes, Arimondo, Paola B., Leonhardt, Heinrich, Kanemaki, Masato T., Bartke, Till, Fachinetti, Daniele, Jeltsch, Albert, Ito, Takashi, Defossez, Pierre-Antoine
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Sprache:eng
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Zusammenfassung: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. DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-47314-4