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Mike Tyers

Co-workers:

Co-workers: Emilie Castonguay, Aileen Greig, Joanna Koszela, Vassiliki Lazou, Lindsay Ramage, Hille Tekotte, Kim Webb, Jan Wildenhain
Tyers lab

Biological networks that control cell growth, division and proteostasis

All cells, from yeast to human, must coordinate cell growth with division, typically before commitment to cell division in late G1 phase. We have used systematic phenotypic and genetic screens in budding yeast to reveal hundreds of factors that influence the balance between growth and division, which is manifest as a characteristic cell size. A notable feature of these screens is the diversity of cellular processes that influence cell size. For example, we have recently discovered that an Rb-like inhibitor of G1/S transcription called Whi5 is intimately linked to mitochondrial function. In a genetic screen for new cell size regulators that interact with Whi5, the majority of yeast gene deletions that were inviable when Whi5 is over-expressed encoded known mitochondrial factors. Whi5 may thus couple mitochondrial function, replication and segregation to the cell division cycle.

We have demonstrated a link between mitochondrial membrane potential and cell size, and shown that inhibitors of mitochondrial membrane potential, but not other mitochondrial functions, cause a small cell size (Figure 1A). In a related screen for deletions that bypass the requirement for known G1/S activators, we have identified a nutrient-regulated factor that appears to reconfigure control of the G1/S transcriptional machinery.

We have also used mass spectrometry to uncover novel nutrient-regulated mechanisms that control metabolic activity at the level of enzyme localization. In parallel, we have used genome-wide approaches to chart chemical genetic space. Hundreds of small molecule screens have enabled us to identify synergistic combinations of molecules that target fungal pathogens, while screens with focused libraries of bioactive compounds against budding yeast, fission yeast, nematodes, worms, zebrafish, thale cress and mammalian cell lines have uncovered many new chemical probes for biological function, including new mitochondrial inhibitors.

We have also undertaken screens to identify compounds that alter heterochromatin formation or inhibit enzymes in the ubiquitin-proteasome system (UPS). Finally, we have continued to expand our open-access protein, genetic and chemical interaction databases (see www.thebiogrid.org and http://tyerslab.bio.ed.ac.uk/molclass/).

Notably, we have recently completed a massive curation effort to systematically capture all of the >50,000 documented interactions in the human UPS (Figure 1B). These database resources have enabled the international research community to understand gene function and to interrogate the structure of cellular regulatory networks

Selected publications:

Selected Publications: Chatr-Aryamontri A, Breitkreutz BJ, Heinicke S, Boucher L, Winter A, Stark C, Nixon J, Ramage L, Kolas N, O’Donnell L, Reguly T, Breitkreutz A, Sellam A, Chen D, Chang C, Rust J, Livstone M, Oughtred R, Dolinski K, Tyers M. (2013) The BioGRID interaction database: 2013 update. Nucleic Acids Res. 41:D816-23.

Tang X, Orlicky S, Mittag T, Csizmok V, Pawson T, Forman-Kay JD, Sicheri F and Tyers M. (2012) Composite low affinity interactions set a multisite phosphorylation threshold for recognition of Sic1 by the SCFCdc4 ubiquitin ligase. Proc Natl Acad Sci USA 109:3287-3292.

Spitzer M†, Griffiths E†, Blakely KM, Wildenhain J, Ejim J, Rossi L, De Pascale G, Curak J, Brown E, Tyers M*, Wright GD* (2011) Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol Sys Biol 7, 499.