Global network analysis of phenotypic effects: Protein networks and toxicity modulation in Saccharomyces cerevisiae

Abstract

Using genome-wide information to understand holistically how cells function is a major challenge of the postgenomic era. Recent efforts to understand molecular pathway operation from a global perspective have lacked experimental data on phenotypic context, so insights concerning biologically relevant network characteristics of key genes or proteins have remained largely speculative. Here, we present a global network investigation of the genotype͞ phenotype data set we developed for the recovery of the yeast Saccharomyces cerevisiae from exposure to DNA-damaging agents, enabling explicit study of how protein-protein interaction network characteristics may be associated with phenotypic functional effects. We show that toxicity-modulating proteins have similar topological properties as essential proteins, suggesting that cells initiate highly coordinated responses to damage similar to those needed for vital cellular functions. We also identify toxicologically important protein complexes, pathways, and modules. These results have potential implications for understanding toxicity-modulating processes relevant to a number of human diseases, including cancer and aging.DNA damage ͉ graph theory ͉ DNA repair ͉ signaling ͉ systems and computational biology C ells represent complex systems with thousands of proteins, carbohydrates, lipids, nucleic acids, and small molecules interacting to maintain growth and homeostasis. Such maintenance requires that cells appropriately respond to both endogenous and exogenous environmental cues. The recent completion of several genome projects provided us with parts lists of genes and proteins that contribute to maintaining growth and homeostasis. Our current challenge is to use this information, along with other extensive data sets, to understand how cells operate in an integrated manner to carry out phenotypic functions. Toward this goal, thousands of protein-protein interactions and genetic interactions have been mapped into complex networks for several organisms (1-10). Although some global network analysis has been performed on these interacting networks, such analyses have rarely been connected with systematic global genotype͞phenotype information. Here we connect protein-protein interaction maps for the budding yeast Saccharomyces cerevisiae with a genomic-scale data set describing the phenotypic role of all nonessential yeast proteins in modulating toxicity after exposure to a number of DNA-damaging agents typical of those encountered in our endogenous and exogenous environment.Graph theoretic approaches are now being used to study global properties of biological networks (11-23). However, network analyses are mostly carried out in the absence of functional information, and when functional information is present it is usually based on cataloged information assembled from an array of unrelated experiments. Tools permitting systematic network perturbations are crucial for establishing biologically meaningful network characteristics, and the S. cerevisiae single-gene deletion strain...

Global Analysis of Protein Damage by the Lipid Electrophile 4-Hydroxy-2-nonenal

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