High-confidence mapping of chemical compounds and protein complexes reveals novel aspects of chemical stress response in yeast

Abstract

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. To uncover previously overlooked players in resistance to chemical stress we integrated several independent chemical genetics datasets with protein–protein interactions and a comprehensive collection of yeast protein complexes. As a consequence we were able to identify the potential targets and mode of action of certain poorly understood compounds. However, most complexes recovered in our analysis appear to perform indirect roles in countering deleterious effects of chemicals by constituting an underlying intricate buffering system that has been so far under-appreciated. This buffering role appears to be largely contributed to by complexes pertaining to chromatin and vesicular dynamics. The former set of complexes seems to act by setting up or maintaining gene expression states necessary to protect the cell against chemical effects. Among the latter complexes we found an important role for specific vesicle tethering complexes in tolerating particular sets of compounds, indicating that different chemicals might be routed via different points in the intracellular trafficking system. We also suggest a general operational similarity between these complexes and molecular capacitors (e.g. the chaperone Hsp90). Both have a key role in increasing the system’s 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.