AbstractIn eukaryotes, DNA methylation is an important epigenetic modification involved in gene regulation. This methylation is catalyzed by DNA (cytosine-5) methyltransferases (DNMTs). In normal cells, DNA methylation is involved, inter alia, in cell differentiation, embryonic development, X-chromosome inactivation and maintenance of chromosomal stability. However, in most cancers, this methylation process is deregulated and leads to the development and progression of tumor cells. As this modification is a reversible process, inhibitors targeting DNMTs are promising anticancer agents to reverse the deregulated methylome to stop cancer proliferation.
This thesis deals with the structural study of non-nucleoside inhibitors of DNMTs. In particular, we studied maleimide derivatives of RG108 (RG108-1 and RG119-1). These compounds have the potential to reactivate tumor suppressor genes silenced by methylation of their promoter. We showed that these covalent inhibitors have better selectivity and inhibitory potency towards DNMTs. Structural and in vitro studies of the various systems of DNMTs aimed to develop a docking protocol to determine their mode of action. We were also interested in a post-translational modification of histones, the trimethylation of lysine 36 of histone 3 (H3K36me3). This epigenetic mark allows the recruitment of DNMT3s, via their PWWP domain, to genomic regions involved in oncogenesis. The structural resolution of this biological system (DNMT3B PWWP domain with the histone mark H3K36me3) and the construction of a complete model of the DNMT3A in complex with a dinucleosome allowed us to propose a genomic recognition mechanism for DNMT3s. This complex led us to identify new potential inhibitors disrupting the interaction between the histone mark H3K36me3 and the DNMT3s PWWP domain. The inhibition of this protein-protein interaction would prevent the intragenic methylation of oncogenes, which is responsible for their transcription.
|Date of Award||13 Dec 2016|
|Sponsors||FONDS SPECIAL DE RECHERCHE (FSR) & FRS-FNRS-Télévie|
|Supervisor||Johan Wouters (Supervisor), Daniel Vercauteren (President), Paulette Charlier (Jury), Luc WILLEMS (Jury), Xavier De Bolle (Jury) & STEVE LANNERS (Jury)|
Attachment to an Research Institute in UNAMUR
- DNA methylation
- PWWP domain
- Epigenetic therapy
- Protein Structures
- DNMT inhibitors
- Protein-protein interaction inhibitors