A genome-scale genetic interaction map was constructed by examining 5.4 million gene-gene pairs for synthetic genetic interactions, generating quantitative genetic interaction profiles for ~75% of all genes in the budding yeast, Saccharomyces cerevisiae. A network based on genetic interaction profiles reveals a functional map of the cell in which genes of similar biological processes cluster together in coherent subsets, and highly correlated profiles delineate specific pathways to define gene function. The global network identifies functional cross-connections between all bioprocesses, mapping a cellular wiring diagram of pleiotropy. Genetic interaction degree correlated with a number of different gene attributes, which may be informative about genetic network hubs in other organisms. We also demonstrate that extensive and unbiased mapping of the genetic landscape provides a key for interpretation of chemical-genetic interactions and drug target identification.

Eukaryotic cells have developed mechanisms for regulating the nuclear transport of macromolecules that control various cellular events including movement through defined stages of the cell cycle. In yeast cells, where the nuclear envelope remains intact throughout the cell cycle, these transport regulatory mechanisms must also function during mitosis. We have uncovered a mechanism for regulating transport that is controlled by M phase specific molecular rearrangements in the nuclear pore complex (NPC). These changes allow a transport inhibitory nucleoporin, Nup53p, to bind the karyopherin Kap121p specifically during mitosis, slowing its movement through the NPC and inducing cargo release. Yeast strains that possess defects in the function of Kap121p or the fidelity of the inhibitory pathway are delayed in mitosis. We propose that fluctuations in Kap121p transport mediated by the NPC contribute to controlling the subcellular distribution of molecules that direct progression through mitosis.

Hsp90 is a ubiquitous and essential molecular chaperone that plays central roles in many signaling and other cellular pathways. The in vivo and in vitro activity of Hsp90 depends on its association with a wide variety of cochaperones and cofactors, which form large multi-protein complexes involved in folding client proteins. Based on our proteomic work mapping the molecular chaperone interaction networks in yeast, especially that of Hsp90, as well as, on experiments and results presented in the published literature, one major role of Hsp90 appears to be the promotion and maintenance of proper assembly of protein complexes. To highlight this role of Hsp90, the effect of the chaperone on the assembly of the following seven complexes is discussed in this review: snoRNP, RNA polymerase II, phosphatidylinositol-3 kinase-related protein kinase (PIKK), telomere complex, kinetochore, RNA induced silencing complexes (RISC), and 26S proteasome. For some complexes, it is observed that Hsp90 mediates complex assembly by stabilizing an unstable protein subunit and facilitating its incorporation into the complex; for other complexes, Hsp90 promotes change in the composition of that complex. In all cases, Hsp90 does not appear to be part of the final assembled complex. This article is part of a Special Issue entitled:Heat Shock Protein 90 (HSP90).

Systematic functional genomics approaches were used to map a network centered on the small ubiquitin-related modifier (SUMO) system. Over 250 physical interactions were identified using the SUMO protein as bait in affinity purification-mass spectrometry and yeast two-hybrid screens. More than 500 genes and 1400 synthetic genetic interactions were mapped by synthetic genetic array (SGA) analysis using eight different SUMO pathway query genes. The resultant global SUMO network highlights its role in 15 major biological processes and better defines functional relationships between the different components of the SUMO pathway. Using this information-rich resource, we have identified roles for the SUMO system in the function of the AAA ATPase Cdc48p, the regulation of lipid metabolism, localization of the ATP-dependent endonuclease Dna2p, and recovery from the DNA-damage checkpoint.

This study defines a network of synthetic sick/lethal interactions with a set of query genes in a series of isogenic cancer cell lines. Analysis of differential essentiality reveals general properties in genetic interaction networks derived from studies on model organisms.