Functional Repurposing Revealed by Comparing S. pombe and S. cerevisiae Genetic Interactions

• Published in: Cell Vol. 149; no. 6; pp. 1339 - 1352
• Main Authors: Frost, Adam, Elgort, Marc G., Brandman, Onn, Ives, Clinton, Collins, Sean R., Miller-Vedam, Lakshmi, Weibezahn, Jimena, Hein, Marco Y., Poser, Ina, Mann, Matthias, Hyman, Anthony A., Weissman, Jonathan S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2012
• Subjects: Biological Evolution; Centrosomes; complexing; Conservation; divergent evolution; Endosomal Sorting Complexes Required for Transport - metabolism; Epistasis, Genetic; Evolution; Gene mapping; genes; Genetic relationship; genetic relationships; genetics; Glucosyltransferase; Mammalian cells; mammals; Membrane Glycoproteins; membranes; Mitosis; Multiprotein Complexes - metabolism; nuclear membrane; Nuclear membranes; Nuclease; nucleases; Protein Interaction Maps; Protein Serine-Threonine Kinases; proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins; Schizosaccharomyces - cytology; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Spindle Apparatus; spindle pole body; stress response; Unfolded Protein Response; yeasts
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2012.04.028

We present a genetic interaction map of pairwise measures including ∼40% of nonessential S. pombe genes. By comparing interaction maps for fission and budding yeast, we confirmed widespread conservation of genetic relationships within and between complexes and pathways. However, we identified an important subset of orthologous complexes that have undergone functional “repurposing”: the evolution of divergent functions and partnerships. We validated three functional repurposing events in S. pombe and mammalian cells and discovered that (1) two lumenal sensors of misfolded ER proteins, the kinase/nuclease Ire1 and the glucosyltransferase Gpt1, act together to mount an ER stress response; (2) ESCRT factors regulate spindle-pole-body duplication; and (3) a membrane-protein phosphatase and kinase complex, the STRIPAK complex, bridges the cis-Golgi, the centrosome, and the outer nuclear membrane to direct mitotic progression. Each discovery opens new areas of inquiry and—together—have implications for model organism-based research and the evolution of genetic systems. [Display omitted] ► Genetic interaction data set for 40% of nonessential S. pombe genes ► Mapping of functional divergence between orthologous genes in two eukaryotes ► Discovery of ER stress-response and spindle-pole-body duplication determinants ► Mitotic STRIPAK signaling complexes bridge centrosomes, nuclear envelope, and Golgi Comparing a genetic interaction map for S. pombe with existing maps for S. cerevisiae identifies a subset of complexes that have undergone functional repurposing and reveals mechanisms of organelle homeostasis and mitosis control. One particular example presents a detailed view of the signaling complex connecting Golgi morphology, cytokinesis, and cell-cycle phasing to highlight the functional reassignments of conserved proteins across evolution.