Mechanisms safe-guarding genome integrity during mammalian cell division

哺乳动物细胞分裂过程中保护基因组完整性的机制

• 批准号: 2273896
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2273896
• 关键词: Mechanisms; safe; guarding; genome; integrity

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.

在有丝分裂中，染色体向子细胞的准确分配对于确保细胞、组织和生物体的活力至关重要。这一过程中的缺陷导致基因组不稳定-表现为细胞死亡和癌症等疾病。真核细胞采用分子监视机制，“纺锤体组装检查点”（SAC），通过称为动粒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的广泛原理是已知的，但关于SAC蛋白如何相互作用并实现其功能的一些分子细节仍然缺乏。特别地，不完全理解的是，不正确地连接的动粒是如何招募和激活关键的SAC调节器以打开纺锤体组装检查点的。该项目旨在研究，在体内和体外，哺乳动物主SAC激酶MPS 1与动粒的相互作用。一系列多学科技术，包括荧光显微镜，基因工程和蛋白质生物化学将用于研究MPS 1和下游SAC蛋白的兴趣。定量图像处理和统计将作为数据集分析的关键技能。