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Updated: Mar 23, 2026
Growth-based Determination and Biochemical Confirmation of Genetic Requirements for Protein Degradation in Saccharomyces cerevisiae
Published on: February 16, 2015
Yeast as a tool to select inhibitors of the cullin deneddylating enzyme Csn5
Angela Cirigliano1,2, Alessandro Stirpe1, Sergio Menta3
1a Istituto Pasteur Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University of Rome , Rome , Italy .
Abstract:
The CSN complex plays a key role in various cellular pathways: through a metalloprotease activity of its Csn5 deneddylating enzyme, it regulates the activity of Cullin-RING ligases (CRLs). Indeed, Csn5 has been found amplified in many tumors, but, due to its pleiotropic effects, it is difficult to dissect its function and the involvement in cancer progression. Moreover, while growing evidences point to the neddylation function as a good target for drug development; specific inhibitors have not yet been developed for the CSN. Here, we propose the yeast Saccharomyces cerevisiae as a model system to screen libraries of small molecules as inhibitors of cullins deneddylation, taking advantage of the unique feature of this organism to survive without a functional CSN5 gene and to accumulate a fully neddylated cullin substrate. By combining molecular modeling and simple genetic tools, we were able to identify two small molecular fragments as selective inhibitors of Csn5 deneddylation function.
Insights
Researchers identified two small molecules that inhibit Csn5 deneddylation. This discovery in yeast offers a new avenue for developing targeted cancer drugs by focusing on the COP9 signalosome (CSN) complex and its role in neddylation.
Area of Science:
- Cellular Biology
- Biochemistry
- Drug Discovery
Background:
- The COP9 signalosome (CSN) complex regulates Cullin-RING ligases (CRLs) via its Csn5 deneddylating enzyme.
- Csn5 is implicated in various cancers, but its complex functions hinder targeted drug development.
- Targeting neddylation pathways presents a promising strategy for cancer therapeutics.
Purpose of the Study:
- To identify selective inhibitors of Csn5 deneddylation.
- To establish Saccharomyces cerevisiae as a model for screening CSN inhibitors.
- To explore the role of Csn5 in cancer progression.
Main Methods:
- Utilized Saccharomyces cerevisiae as a model organism for high-throughput screening.
- Employed molecular modeling to guide inhibitor identification.
- Combined genetic tools with small molecule screening.
Main Results:
- Identified two small molecular fragments that selectively inhibit Csn5 deneddylation.
- Demonstrated the utility of yeast for screening CSN inhibitors.
- Showcased the accumulation of fully neddylated cullin substrates in yeast.
Conclusions:
- Saccharomyces cerevisiae is a viable model for discovering CSN inhibitors.
- The identified small molecules represent potential leads for anti-cancer drug development.
- Selective inhibition of Csn5 deneddylation is achievable and warrants further investigation.
