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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