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Yamaguchi, K.* ; Chen, X.* ; Rodgers, B.* ; Miura, F.* ; Bashtrykov, P.* ; Bonhomme, F.* ; Salinas-Luypaert, C.* ; Haxholli, D.* ; Gutekunst, N.* ; Özdemir Aygenli, B. ; Ferry, L.* ; Kirsh, O.* ; Laisné, M.* ; Scelfo, A.* ; Ugur, E.* ; Arimondo, P.B.* ; Leonhardt, H.* ; Kanemaki, M.T.* ; Bartke, T. ; Fachinetti, D.* ; Jeltsch, A.* ; Ito, T.* ; Defossez, P.A.*

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

Nat. Commun. 15:2960 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Methyltransferase Dnmt1; Protein Uhrf1; Sra Domain; Recognition; Set; Interacts; Base
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 2960 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Functional Epigenetics (IFE)
Grants CNRS Epigenetics and Cell Fate Unit
Agence Nationale de la Recherche
Fondation ARC (ARC labellisation program 2019)
Institut National du Cancer
Universit de Paris IdEx
JSPS Overseas Research Fellowships
Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED
Deutsche Forschungsgemeinschaft
Foundation DFG
Cell and Tissue Imaging (PICT-IBiSA)
Institut Curie
Region Ile-de-France
Fondation Bettencourt Schueller
Agence Nationale de la Recherche (French National Research Agency)