Biology subjects

Bourgine, G.

Publications and source records attributed to Bourgine, G..

2 recordsLinked to original sources

bioRxiv2023

Targeting fungal BET bromodomains as a pan-Candida antifungal strategy

Small molecules that target one or both bromodomains (BDs) of human BET proteins are intensely studied as potential new therapeutics against cancer, diabetes and other diseases. The BDs of the fungal BET protein Bdf1 are essential for the human fungal pathogen Candida albicans, suggesting BET inhibition as a potential antifungal strategy. However, while the inactivation of both Bdf1 BDs is lethal, that of a single BD only modestly affects viability, implying the need to develop antifungal compounds that selectively target both Bdf1 BDs without inhibiting human BDs. Here, we investigate Bdf1 as a potential antifungal target in Candida glabrata, an invasive Candida species phylogenetically distant from C. albicans and of increasing medical concern. We show that Bdf1 BD functionality is essential in C. glabrata and identify a phenyltriazine derivative that targets both Bdf1 BDs with selectivity over human BET BDs. We show that human BET BDs can functionally replace Bdf1 BDs in C. glabrata and we use the humanized strains to demonstrate on-target antifungal activity of the phenyltriazine compound. Moreover, by exploiting the humanized and parental fungal strains we identified BET inhibitor I-BET726 to have potent antifungal activity against a broad spectrum of Candida species, including azole- and echinocandin-resistant clinical C. albicans and C. glabrata isolates. Crystal structures suggest how to improve the potency and selectivity of these compounds. Taken together, our findings provide compelling support for the development of BET inhibitors as potential pan-Candida antifungal therapeutics.

biochemistry↗

bioRxiv2021

The histone methyltransferase NSD3 contributes to cohesin loading during mitotic exit

Sister chromatid cohesion guarantees the correct transmission of chromosomes to daughter cells, and this multi-step process occurs throughout the cell cycle. Loading of the core cohesin complex onto chromatin takes place during mitotic exit, cohesion establishment happens during DNA replication, and the timely removal of cohesin occurs during mitosis. While cohesion establishment and mitotic cohesion dissolution have already been explored, the regulation of cohesin loading is not as well understood. Here, we report that the histone-lysine N-methyltransferase NSD3 is an essential factor in sister chromatid cohesion and mitotic progression, and that this occurs before and not after entry into mitosis. We establish that NSD3 interacts with the cohesin loader complex kollerin (NIPBL/MAU2), and that at mitotic exit it ensures proper levels of both MAU2 and cohesin itself on chromatin. In accordance with this newly described function in cohesin loading, we also show that NSD3 associates with chromatin in early anaphase, prior to the loading recruitment of MAU2 and RAD21, and that it then dissociates from chromatin when prophase begins. Going further, we also demonstrate that of the two NSD3 variants existing in somatic cells, it is the long isoform that is responsible for regulating kollerin and cohesin chromatin-loading, and that this isoforms methyltransferase activity is required for efficient sister chromatid cohesion. Based on these observations, we propose that NSD3-dependent methylation contributes to sister chromatid cohesion by ensuring the proper recruitment of kollerin and thus loading of cohesin.

molecular biology↗