S.cerevisiae as a tool to select inhibitors of the deneddylating activity of the COP9 signalome Angela Cirigliano, Sergio Menta, Mattia Mori, Valerio Licursi, Svetlana Danovska, Valentina Vapore, Giovanna Serino, Elah Pick, Bruno Botta, Rodolfo Negri, and Teresa Rinaldi

The COP9 signalosome (CSN) protein complex plays a key role in regulating cullin-RING ligases and is a central mediator of cellular functions essential for cancer progression. The CSN5/Jab1 gene, encoding the catalytic subunit of the complex, has been found amplified in many tumors; however, due to its pleiotropic effects, it has been difficult to dissect Csn5 function and its involvement in cancer progression. Moreover, while a growing body of evidence point to the neddylation pathway as a good target for drug development, specific inhibitors have not yet been developed for the Csn5 enzyme. Deneddylation by the CSN is conserved in the budding yeast Saccharomyces cerevisiae and, in contrast to human or plants, lack of Csn5 does not compromise viability of budding yeast. We have recently performed a transcriptomic and proteomic analysis of a csn5 strain to assess its function in budding yeast, and we have shown that Csn5 is involved in the modulation of the genes controlling amino acid and lipid metabolism and in particular of the ergosterol biosynthesis; this observation correlates with lower ergosterol level in csn5 cells (Licursi et al., (2014). FEBS Journal, 281(1), 175-190) In the study shown here, we have used budding yeast as a model to identify novel inhibitors of Csn5 deneddylating activity. We present our preliminary results obtained using a combined approach of molecular modelling and simple genetic tools to identify small molecules as selective inhibitors of Csn5 deneddylating function