Molecular Genetic Analysis of Regulatory Networks Governing Cytokinesis

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Research within the lab focuses on the regulatory networks required to bring about the successful completion of cytokinesis in the model eukaryote, Schizosaccharomyces pombe. While previous work in the field has centered on the cytoskeletal structures and forces required to bring about cleavage in cells grown under ideal conditions, our goals are to better understand the genetic regulatory networks required to prevent cytokinesis failure when cells are subject to stresses that impede the cell division process. The foundation of the current proposal stems from recent work supporting the existence of a cytokinesis "monitoring system". Upon perturbation of the cell division machinery, this system has the capacity to both delay cell cycle progression and stabilize the cytokinetic actomyosin ring. The biological importance of such mechanisms have been substantiated by the demonstration that tetraploid intermediates (produced upon cytokinesis failure) show a markedly increased potential for tumourigenesis. Thus, an understanding of these networks has the potential to provide insight into the mechanisms important for maintaining genomic integrity in eukaryotes. The current proposal revolves around the molecular and genetic analysis of previously uncharacterized regulatory networks required for the proper function and/or regulation of the cytokinesis monitoring system. These pathways were identified through the execution of a recent genome-wide screen that assayed fission yeast gene deletion mutants for hypersensitivity to Latrunculin A (an actin depolymerizing drug used as a tool to perturb the cell division machinery). As expected this screen identified many genes with roles in the regulation of cytoskeletal dynamics and/or cytokinesis. In addition, many other unexpected "hits", identifying genes affecting biological processes such as stress-dependent signaling, histone acetylation/de-acetylation, and transcriptional control were also identified. Using the lab's expertise in molecular biology, genetic analysis, and fluorescence microscopy, our objectives are to characterize the identified regulatory complexes in order to provide a comprehensive, genome-wide picture of the genetic regulatory wiring and molecular mechanisms required by a model eukaryotic cell to faithfully and reliably execute cytokinesis.