Mechanisms safe-guarding genome integrity during mammalian cell division

在有丝分裂过程中，准确地将染色体分割成子代细胞对于确保细胞、组织和生物体的活力是至关重要的。这一过程中的缺陷会导致基因组不稳定--表现为细胞死亡和癌症等疾病。真核细胞利用一种名为纺锤体组装检查点(SAC)的分子监测机制，通过称为动点的结构来监测染色体与有丝分裂纺锤体的正确连接，从而确保有丝分裂期间基因组的忠实分离。虽然SAC的广泛原理已为人所知，但关于SAC蛋白如何相互作用和实现其功能的一些分子细节仍然缺乏。特别是，人们对未正确连接的动轴如何招募和激活关键的SAC调节器以打开主轴组件检查点的确切了解还不完全。该项目试图在体内和体外研究哺乳动物主要的SAC激酶Mps1与动素中心的相互作用。包括荧光显微镜、基因工程和蛋白质生物化学在内的一系列多学科技术将被用于研究Mps1和下游感兴趣的SAC蛋白质。定量图像处理和统计将成为分析数据集的关键技能。

The accurate partitioning of chromosomes to daughter cells in mitosis is essential for ensuring the viability of cells, tissues, and organisms. Defects in this process lead to genomic instability - manifesting as cell death and diseases such as cancer. Eukaryotic cells employ a molecular surveillance mechanism, the "spindle assembly checkpoint" (SAC), to monitor the proper attachment of chromosomes to the mitotic spindle via structures called kinetochores - thus ensuring faithful segregation of the genome during mitosis. While the broad principles of the SAC are known, some of the molecular details about how SAC proteins interact and fulfil their function is still lacking. In particular, it is incompletely understood precisely how improperly attached kinetochores recruit and activate key SAC regulators to turn on the spindle assembly checkpoint. This project seeks to study, in vivo and in vitro, the interaction of the mammalian master SAC kinase MPS1 with kinetochores. A range of multidisciplinary techniques including fluorescence microscopy, genetic engineering, and protein biochemistry will be used to study MPS1 and downstream SAC proteins of interest. Quantitative image processing and statistics will serve as key skills for the analysis of datasets.