Fiche publication
Date publication
juillet 2019
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BRONNER Christian
,
Pr MELY Yves
,
Dr RUFF Marc
,
Dr RICHERT Ludovic
,
Dr MOUSLI Marc
Tous les auteurs :
Zaayter L, Mori M, Ahmad T, Ashraf W, Boudier C, Kilin V, Gavvala K, Richert L, Eiler S, Ruff M, Botta M, Bronner C, Mousli M, Mely Y
Lien Pubmed
Résumé
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 of UHRF1. 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.
Mots clés
DNA methylation, virtual screening, fluorescence, base flipping inhibitor
Référence
Chemistry. 2019 Jul 19;:
