Chemical network analysis reveals a system of chromatin and trafficking level backups in the cell

Chemical genetics in yeast has shown great potential for clarifying the pharmacology of various drugs. Investigating these results from a systems perspective has uncovered many facets of natural chemical tolerance, but many cellular interactions of chemicals still remain poorly understood. We integrated several independent chemical genetics datasets with protein–protein interactions and a comprehensive collection of yeast protein complexes. We found potential targets and mode of action of certain poorly understood compounds. Intriguingly, the majority of the complexes in our network probably perform indirect roles in countering deleterious effects of chemicals. We propose that they form underlying buffering system that has been so far over-looked. Such complexes are basically composed of two classes: chromatin and vesicular dynamics. The former set of complexes seems to act by setting up or maintaining transcriptional programs necessary to protect the cell against chemical effects. On the other hand, the latter include specific vesicle tethering complexes, indicating that different chemicals might be routed via different points in the intracellular trafficking system. We propose a general operational similarity between these complexes and molecular capacitors (e.g. the chaperone Hsp90). Both have a key role in increasing the systems robustness, although at different levels, through buffering stress and mutation, respectively. It is therefore conceivable that some of these complexes identified here might have roles in molding the evolution of chemical resistance and response.

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The yeast Ubiquitin network

In this paper we assembled a comprehensive network of the ubiquitin system (Ub-system), namely ubiquitin-like proteins, their conjugation and deconjugation apparatus, binding partners and the proteasomal system. To achieve the best possible network, we integrated numerous ubiquitination/sumoylation datasets with public protein/genetic interaction databases. To aid in the data analysis, we devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system. Using these representations, we found supporting evidence for the functional diversification of SUMO-dependent Ub-ligases. We also identify novel components of SCF complexes, receptors in the ERAD system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics. We also identified several modified transcription factors, suggesting an extensive regulatory impact of the Ub system in the cellular networks. Furthermore, the dynamics of the Ub-network suggests that Ub and SUMO modifications might function cooperatively with transcription control in regulating cell-cycle-stage-specific complexes and in reinforcing periodicities in gene expression. Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

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Reconstructing the Yeast Ubiquitin network

Watch this space for more details. For now, please read the full manuscript.

Reconstructing the ubiquitin network - cross-talk with other systems and identification of novel functions. Venancio TM, Balaji S, Iyer LM, Aravind L. Genome Biol. 2009 Mar 30;10 (Click here to read).