Condensin and Chromosome Segregation in C. elegans

描述（由申请人提供）：在每次细胞分裂期间，基因组必须准确复制并将一组完整的染色体分离到每个子细胞中。染色体分离失败会对人类健康产生严重后果，因为产生染色体数目不合适的细胞可能导致细胞死亡、出生缺陷或癌症。我们研究的长期目标是定义控制染色体分离的分子机制和机制，以确保基因组稳定性。该提案的重点是凝缩蛋白复合物，即染色体组织和分离的保守关键调节因子。凝缩蛋白在减数分裂和有丝分裂染色体分离之前结合并重新配置，并且被认为是通过使用 ATP 水解将 DNA 缠绕成大环来实现的。我们试图了解多个凝缩蛋白复合物的功能和组成，这并不像最初想象的那么简单。使用模型生物秀丽隐杆线虫，我们发现凝缩蛋白不是一个简单的压缩因子，而是在姐妹染色单体分辨率和着丝粒组织中发挥着更复杂的作用。我们还证明了两种凝缩蛋白复合物的存在，它们具有重叠的成分，但在有丝分裂和 X 染色体基因调控中具有不同的功能。人们已经清楚，人类细胞还含有两种有丝分裂所必需的凝缩蛋白（凝缩蛋白 I 和 II），但具有不同的染色体定位、功能和调节。关于凝缩蛋白尚未解答的重要问题包括确定每个复合物执行的精确功能、这些功能在多大程度上是独特的或冗余的，以及这些功能如何通过细胞周期和发育进行差异调节。在初步研究中，我们鉴定了额外的凝缩蛋白 I 和 II 亚基，为凝缩蛋白 I 在染色体分离中发挥作用提供了证据，并鉴定了可能将凝缩蛋白功能与细胞周期联系起来的激酶。我们建议：1）确定秀丽隐杆线虫复合体的组成和数量，并鉴定其相关蛋白。 2) 确定不同凝缩蛋白复合物在有丝分裂、减数分裂和基因调控中的不同功能。 3) 确定凝缩蛋白如何受细胞周期激酶调节。这项研究将深入了解细胞如何确保细胞分裂过程中遗传物质的准确分布，并避免流产和实体瘤中常见的染色体错误。

DESCRIPTION (provided by applicant): During every cell division, the genome must accurately replicate and segregate a complete set of chromosomes into each daughter cell. Failures in chromosome segregation have severe consequences for human health, since creating cells with an inappropriate chromosome number can lead to cell death, birth defects, or cancer. The long-term goal of our research is to define the molecular machinery and mechanisms that govern chromosome segregation to ensure genomic stability. This proposal focuses on condensin protein complexes, conserved key regulators of chromosome organization and segregation. Condensins bind and reconfigure meiotic and mitotic chromosomes prior to their segregation, and are thought to do so by using ATP hydrolysis to wind DNA into large loops. We seek to understand the functions and composition of the multiple condensin complexes, which are not as straightforward as originally thought. Using the model organism C. elegans, we showed that condensin is not a simple compaction factor, but plays more complex roles in sister chromatid resolution and centromere organization. We also demonstrated the existence of two condensin complexes with overlapping components but distinct functions in mitosis and X chromosome gene regulation. It has since become clear that human cells also contain two condensins (condensin I and II) both necessary for mitosis but having distinct chromosome localization, function, and regulation. Important unanswered questions about condensins include determining the precise function each complex performs, to what extent these functions are unique or redundant, and how these functions are differentially regulated through the cell cycle and development. In preliminary studies we identified additional condensin I and II subunits, provided evidence for a condensin I that functions in chromosome segregation, and identified kinases that may tie condensin function to the cell cycle. We propose to: 1) Determine the composition and number of C. elegans complexes and identify their associated proteins. 2) Determine the distinct functions of different condensin complexes in mitosis, meiosis, and gene regulation. 3) Determine how condensin is regulated by cell cycle kinases. This research will provide insight into how cells ensure accurate distribution of the genetic material during cell division, and avoid the chromosomal errors often observed in miscarriages and solid tumors.