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

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 relevan...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 52; pp. 18006 - 18011
Main Authors Said, M.R, Begley, T.J, Oppenheim, A.V, Lauffenburger, D.A, Samson, L.D
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.12.2004
National Acad Sciences
Subjects
bioinformatics
Biological Sciences
Cellular biology
Cluster Analysis
Computational Biology
Databases, Protein
DNA damage
DNA repair
Fungal proteins
gene deletion
Gene Expression Regulation, Fungal
Genes
Genes, Fungal
Genome, Fungal
genomic phenotyping
Genomics
interactome
Models, Biological
Models, Theoretical
Modulated signal processing
mutants
P values
Phenotype
Protein Binding
Protein Conformation
Protein Interaction Mapping
Protein metabolism
protein networks
protein-protein interactions
Proteins
Proteins - chemistry
Proteome
Proteomics
Random allocation
Saccharomyces cerevisiae
Saccharomyces cerevisiae - physiology
single gene deletion
Software
Toxicity
Yeasts
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Summary: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 genotype/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 toxico-logically 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.
Bibliography:To whom correspondence should be addressed. E-mail: lsamson@mit.edu.
M.R.S. and T.J.B. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Present address: Department of Biomedical Sciences, Gen*NY*sis Center for Excellence in Cancer Genomics, University of Albany, Rensselaer, NY 12144.
Abbreviations: MMS, methyl methanesulfonate; 4NQO, 4-nitroquinoline-N-oxide; t-BuOOH, tert-butyl hydroperoxide.
Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved November 3, 2004
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0405996101