Identifying the Molecular Determinants of Chromosome Stability in Humans.

识别人类染色体稳定性的分子决定因素。

• 批准号: 401851-2012
• 负责人: McManus, Kirk
• 金额: $ 2.04万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=628959
• 关键词: Identifying; Molecular; Determinants; Chromosome; Stability

Understanding the molecular bases and processes that impact chromosome stability is of critical importance to all living organisms. Many of the biological processes that impact chromosome stability are inherently conserved throughout evolution, and include DNA replication, repair and chromosome segregation during cellular division. Consequently, information gleaned in model organisms such as yeast, flies and worms can be used to identify candidates to evaluate in a human context. Unbiased and genome-wide approaches have in the past been limited to genetically tractable models such as yeast and have generated lists of chromosome stability genes - many of which remain to be fully characterized. What's more, even less is known about the corresponding human counterparts particularly with respect to their roles in chromosome stability or the underlying mechanism. Recent advancements in genetic approaches, reagents and equipment have now made it possible to perform large-scale analyses in human cell lines. We recently employed a focused cross-species approach and identified new human chromosome stability genes. We subsequently demonstrated that a subset of these genes products are required for sister chromatid cohesion, an essential biological process in which newly replicated chromosomes are held in close together prior to cellular division. Defective sister chromatid cohesion adversely affects chromosome stability by allowing for the inaccurate segregation of genetic material into each daughter cell. We now seek to greatly expand these initial studies by developing an innovative and high-throughput approach in which we will evaluate chromosome stability for candidate human genes identified in cross-species approaches. By coupling state-of-the-art molecular imaging with cutting-edge genetic and biochemical techniques we will rapidly interrogate candidates and produce a refined list of human chromosome stability genes. In turn, these genes will become the subjects of subsequent studies designed to further characterize their specific functional roles in maintaining chromosome stability and will vastly expand current knowledge pertaining to a pivotal biological process that is essential in all living organisms.

了解影响染色体稳定性的分子基础和过程对所有生物体都至关重要。许多影响染色体稳定性的生物过程在整个进化过程中都是固有保守的，包括细胞分裂过程中的DNA复制、修复和染色体分离。因此，在酵母菌、苍蝇和蠕虫等模式生物中收集的信息可用于确定在人类环境中进行评估的候选物。在过去，无偏倚和全基因组的方法仅限于遗传上易于处理的模型，如酵母，并且已经生成了染色体稳定性基因的列表——其中许多仍有待完全表征。更重要的是，我们对人类的相应基因知之甚少，尤其是它们在染色体稳定性或潜在机制中的作用。遗传方法、试剂和设备的最新进展使对人类细胞系进行大规模分析成为可能。我们最近采用了一种集中的跨物种方法，并确定了新的人类染色体稳定性基因。我们随后证明了这些基因产物的一个子集是姐妹染色单体内聚所必需的，这是一个重要的生物学过程，在这个过程中，新复制的染色体在细胞分裂之前紧密地结合在一起。有缺陷的姐妹染色单体内聚会使遗传物质不准确地分离到每个子细胞中，从而对染色体的稳定性产生不利影响。我们现在寻求通过开发一种创新和高通量的方法来极大地扩展这些初步研究，在这种方法中，我们将评估在跨物种方法中鉴定的候选人类基因的染色体稳定性。通过将最先进的分子成像技术与最先进的遗传和生化技术相结合，我们将快速询问候选基因并生成人类染色体稳定基因的精细列表。反过来，这些基因将成为后续研究的主题，旨在进一步表征它们在维持染色体稳定性方面的特定功能角色，并将极大地扩展当前有关所有生物体中必不可少的关键生物过程的知识。