Identifying the Molecular Determinants of Chromosome Stability in Humans.

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学过程在整个进化过程中是固有保守的，包括DNA复制、修复和细胞分裂期间的染色体分离。因此，在酵母、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者。无偏见和全基因组的方法在过去仅限于遗传上易于处理的模型，如酵母，并产生了染色体稳定性基因的列表-其中许多仍然是充分的特点。更重要的是，对相应的人类对应物的了解甚至更少，特别是关于它们在染色体稳定性或潜在机制中的作用。遗传学方法、试剂和设备的最新进展现在使得在人类细胞系中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。随后，我们证明了这些基因产物的一个子集是姐妹染色单体凝聚所必需的，这是一个重要的生物学过程，其中新复制的染色体在细胞分裂前紧密结合在一起。姐妹染色单体凝聚力缺陷会使遗传物质不准确地分离到每个子细胞中，从而对染色体稳定性产生不利影响。我们现在寻求通过开发一种创新的高通量方法来大大扩展这些初步研究，在这种方法中，我们将评估跨物种方法中确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与尖端的遗传和生化技术相结合，我们将快速询问候选人并产生人类染色体稳定性基因的精确列表。反过来，这些基因将成为后续研究的主题，旨在进一步表征其在维持染色体稳定性方面的特定功能作用，并将极大地扩展与所有生物体中必不可少的关键生物过程有关的现有知识。

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.