A Molecular Tool Targeting the Base‐Flipping Activity of Human UHRF1
| Autor: | Christian Bronner, Christian Boudier, Waseem Ashraf, Marc Ruff, Krishna Gavvala, Vasyl Kilin, Tanveer Ahmad, Sylvia Eiler, Marc Mousli, Mattia Mori, Yves Mély, Liliyana Zaayter, Ludovic Richert, Maurizio Botta |
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| Přispěvatelé: | Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Siena = University of Siena (UNISI), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Molecular model Protein Conformation Ubiquitin-Protein Ligases Druggability Drug Evaluation Preclinical Anthraquinones [SDV.CAN]Life Sciences [q-bio]/Cancer Computational biology 010402 general chemistry Transfection 01 natural sciences Methylation Catalysis chemistry.chemical_compound Structure-Activity Relationship Humans base flipping inhibitors DNA methylation fluorescence virtual screening 5-Methylcytosine Binding Sites CCAAT-Enhancer-Binding Proteins Enzyme Inhibitors HeLa Cells Kinetics Molecular Docking Simulation Molecular Structure Protein Binding ComputingMilieux_MISCELLANEOUS Virtual screening 010405 organic chemistry Chemistry Organic Chemistry DNA replication General Chemistry Preclinical 0104 chemical sciences DNMT1 Drug Evaluation DNA |
| Zdroj: | Chemistry-A European Journal Chemistry-A European Journal, Wiley-VCH Verlag, 2019, 25 (58), pp.13363-13375. ⟨10.1002/chem.201902605⟩ |
| ISSN: | 0947-6539 1521-3765 |
| Popis: | During DNA replication, ubiquitin-like, containing PHD and RING fingers domains 1 (UHRF1) plays key roles in the inheritance of methylation patterns to daughter strands by recognizing through its SET and RING-associated domain (SRA) the methylated CpGs and recruiting DNA methyltransferase 1 (DNMT1). Herein, our goal is to identify UHRF1 inhibitors targeting the 5'-methylcytosine (5mC) binding pocket of the SRA domain to prevent the recognition and flipping of 5mC and determine the molecular and cellular consequences of this inhibition. For this, we used a multidisciplinary strategy combining virtual screening and molecular modeling with biophysical assays in solution and cells. We identified an anthraquinone compound able to bind to the 5mC binding pocket and inhibit the base-flipping process in the low micromolar range. We also showed in cells that this hit impaired the UHRF1/DNMT1 interaction and decreased the overall methylation of DNA, highlighting the critical role of base flipping for DNMT1 recruitment and providing the first proof of concept of the druggability of the 5mC binding pocket. The selected anthraquinone appears thus as a key tool to investigate the role of UHRF1 in the inheritance of methylation patterns, as well as a starting point for hit-to-lead optimizations. |
| Databáze: | OpenAIRE |
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