Hot Spots for Modulating Toxicity Identified by Genomic Phenotyping and Localization Mapping

DNA repair and checkpoint pathways protect against carcinogen-induced toxicity. Here, we describe additional, equally protective pathways discovered by interrogating 4,733 yeast proteins for their ability to diminish toxicity induced by four known carcinogens. A computational mapping strategy for gl...

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Bibliographic Details
Published in:Molecular cell 2004-10, Vol.16 (1), p.117-125
Main Authors: Begley, Thomas J., Rosenbach, Ari S., Ideker, Trey, Samson, Leona D.
Format: Article
Language:English
Subjects:
Cell Nucleus - metabolism
Chromosome Mapping
DNA Damage
Endosomes - metabolism
Gene Deletion
Genome
Microtubules - metabolism
Mutagens - toxicity
Saccharomyces cerevisiae
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Vacuoles - metabolism
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Summary:DNA repair and checkpoint pathways protect against carcinogen-induced toxicity. Here, we describe additional, equally protective pathways discovered by interrogating 4,733 yeast proteins for their ability to diminish toxicity induced by four known carcinogens. A computational mapping strategy for global phenotypic data was developed to build a systems toxicology model detailing recovery from carcinogen exposure and identifying protein complexes that modulate toxicity. Global phenotypic data were merged with global subcellular localization and protein interactome data to generate an integrated picture of cellular recovery after carcinogen exposure. Statistically validated results from this systems-wide integration demonstrate that, in addition to the nucleus, subnetworks of toxicity-modulating proteins were overrepresented in the vacuolar membrane, endosome, endoplasmic reticulum, and mitochondrion. In addition, we show that many proteins associated with RNA polymerase II, macromolecular trafficking, and vacuole function can now be counted among the many proteins that modulate carcinogen-induced toxicity.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2004.09.005