Molecular Genetic Analysis of Regulatory Networks Governing Cytokinesis

实验室的研究重点是在真核生物裂糖酵母（Schizosaccharomyces pombe）中成功完成细胞分裂所需的调控网络。虽然该领域之前的工作主要集中在细胞骨架结构和导致细胞分裂所需的力量上，但我们的目标是更好地理解细胞分裂在细胞周期中正确的位置和正确的时间准确发生所需的遗传调控网络。* *当前建议的基础源于最近支持存在细胞分裂“监测系统”的工作。当细胞分裂机制受到干扰时，该系统具有延迟细胞周期进程和稳定细胞动力学肌动球蛋白环的能力。近年来，四倍体中间体（在细胞分裂失败时产生）显示出显著增加的肿瘤发生潜力，证实了这种机制的生物学重要性。因此，对这些网络的理解有可能提供对维持真核生物基因组完整性的重要机制的见解。**目前的建议围绕着几个以前未表征的调节网络的分子和遗传分析，这些网络是细胞分裂监测系统的正常功能和/或调节所必需的。这些途径是通过全基因组筛选确定的，该筛选分析了裂变酵母基因缺失突变体对Latrunculin a（一种肌动蛋白解聚药物，用作扰乱细胞分裂机制的工具）的超敏反应。正如预期的那样，该筛选确定了许多已知在细胞骨架动力学和/或细胞分裂调节中起作用的基因。此外，还发现了许多其他意想不到的“命中”，确定了影响生物过程的基因，如组蛋白乙酰化/去乙酰化和转录控制。**利用实验室在分子生物学、遗传分析和活细胞成像方面的成熟技能，我们的目标是表征已识别的调控复合物，以提供一个完整的、全基因组的遗传调控线路图，这是一个模型真核细胞忠实可靠地执行细胞分裂所必需的。

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 cell cleavage, our goals are to better understand the genetic regulatory networks required for cytokinesis to occur faithfully, at the proper location, and at the proper time during the cell cycle.* *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 in recent years 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 several 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 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 known roles in the regulation of cytoskeletal dynamics and/or cytokinesis. In addition, many other unexpected "hits", identifying genes affecting biological processes such as histone acetylation/de-acetylation and transcriptional control were also identified.**Using the lab's established skill in molecular biology, genetic analysis, and live-cell imaging, our objectives are to characterize the identified regulatory complexes in order to provide a comprehensive, genome-wide picture of the genetic regulatory wiring required by a model eukaryotic cell to faithfully and reliably execute cytokinesis.