[1] Department of Cellular and Molecular Pharmacology, [2] The California Institute for Quantitative Biomedical Research, and, [3] Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA-
Abstract: Defining the functional relationships between proteins is critical for understanding virtually all aspects of cell biology- Large-scale identification of protein complexes has provided one important step towards this goal; however, even knowledge of the stoichiometry, affinity and lifetime of every protein-protein interaction would not reveal the functional relationships between and within such complexes- Genetic interactions can provide functional information that is largely invisible to protein-protein interaction data sets- Here we present an epistatic miniarray profile -E-MAP- consisting of quantitative pairwise measurements of the genetic interactions between 743 Saccharomyces cerevisiae genes involved in various aspects of chromosome biology -including DNA replication-repair, chromatid segregation and transcriptional regulation-- This E-MAP reveals that physical interactions fall into two well-represented classes distinguished by whether or not the individual proteins act coherently to carry out a common function- Thus, genetic interaction data make it possible to dissect functionally multi-protein complexes, including Mediator, and to organize distinct protein complexes into pathways- In one pathway defined here, we show that Rtt109 is the founding member of a novel class of histone acetyltransferases responsible for Asf1-dependent acetylation of histone H3 on lysine 56- This modification, in turn, enables a ubiquitin ligase complex containing the cullin Rtt101 to ensure genomic integrity during DNA replication-