Spatio-temporal control of cytokinesis : regulation of septin dynamics by small GTPases and ubiquitin ligases – SEPTDYN

Cytokinesis is the complex process by which two daughter cells physically separate at the end of cell division. Understanding this process is a very important goal, not only for its basic biological significance, but also for its practical implications. Indeed, cytokinesis failure can lead to polyploid cells that are genetically unstable and undergo more frequently to chromosome missegregation and aneuploidy, eventually leading to cancer development . Septins belong to a family of highly conserved cytoskeletal GTP-binding proteins able to assemble into filaments and higher ordered assemblies, such as rings. Despite fulfilling various cellular functions such as cytoskeleton organization, membrane compartimentalization and cell polarity, septins have been implicated in cytokinesis in many different organisms. Yet their precise function in this process remains to be determined. The links between septins and human pathological conditions, such as cancer, Parkinson and other neurodegenerative diseases, has recently drawn considerable attention onto these proteins. In budding yeast, where they were discovered, septins form a ring at the bud neck, which is the site of cell division. The septin ring undergoes dramatic dynamic transitions during the cell cycle that are likely crucial for its cellular function(s) and are regulated by known and unknown players. Through genetic approaches in budding yeast, we have involved two redundant ubiquitin ligases, Dma1 and Dma2 (homologs of tumor suppressor Chfr), and the GTPases Rho1 (the counterpart of RhoA in higher eukaryotes) in the control of septin ring dynamics. In addition, our data indicate that another GTPase, Tem1, that is required for cytokinesis and is known to regulate septin dynamics, is likely regulated by Dma1/2, providing further evidence for a link between ubiquitylation and GTPase activity in the dynamics of septin rings. This proposal aims at gaining novel insights into the process of septin dynamics and its regulation using the budding yeast S. cerevisiae and the fruit fly D. melanogaster as model systems. In addition, a screen for the human functional homolog of yeast Tem1 promises to open new grounds to investigate the conservation of the mechanisms involved in cytokinesis in eukaryotic cells. We feel that our discoveries will deepen our knowledge of the basic mechanisms involved in cytokinesis and might provide novel insights into the mechanisms contributing to the genesis of cancer.