Télévie: Inhibition of DNA methylation: structural and functional study of the PWWP regulatory domains of DNMT 3A and B.

Our project aims at financing an ongoing PhD thesis on the structural and functional study of PWWP regulatory domains of DNMT 3A and DNMT 3B. These studies are carried out in close collaboration with Prof L.Willems (ULg). Hypermethylation of cytosines by DNMTs is an epigenetic modification that plays a major role in oncology as it can lead to silencing of tumor supressor genes. Inhibition of these DNA methylation enzymes offers new opportunities in the context of design of new anti-cancer therapies. Human DNMT3A and DNMT3B establish the methylation pattern of genes, modulating their expression. The main goal of the project is the identification and the characterization of original ligands (peptides and non peptidic compounds) of the DNMT3A/3B PWWP regulatory domain. Our strategy is based on a complementary structural (crystallography and modelling) and biological (cellular testing) approach. Sofar, our work led to the determination of a series of original complexes with the PWWP domains, in particular a complex with ethambutol. During the two remaining years of the PhD thesis, our goal is to evaluate the interest of ethambutol as a potential anticancer compound.