Condensin and Chromosome Segregation in C. elegans

线虫中的凝缩蛋白和染色体分离

• 批准号: 7143939
• 负责人: KIRSTEN A HAGSTROM
• 金额: $ 29.92万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143939
• 关键词: Caenorhabditis elegans; DNA binding protein; RNA interference; cell cycle; centromere; chromosome movement; cytogenetics; density gradient ultracentrifugation; functional /structural genomics; gender difference; genetic crossing over; genetic regulation; helminth genetics; heterochromatin; immunoprecipitation; meiosis; molecular dynamics; protein protein interaction; protein structure function; serine threonine protein kinase; transfection; yeast two hybrid system

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.

描述（由申请人提供）：在每个细胞分裂期间，基因组必须准确地复制并将一组完整的染色体隔离到每个子细胞中。染色体隔离的失败对人类健康产生了严重的后果，因为创建具有不适当染色体数的细胞会导致细胞死亡，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以确保基因组稳定性的分子机制和机制。该提案的重点是冷凝蛋白蛋白复合物，染色体组织和隔离的保守关键调节剂。冷凝剂在分离之前结合并重新配置减数分裂和有丝分裂染色体，并认为通过使用ATP水解将DNA变成大环。我们试图理解多个冷凝蛋白复合物的功能和组成，这些功能和组成并不像最初想象的那样简单。使用模型生物体秀丽隐杆线虫，我们表明冷凝蛋白不是一个简单的压实因子，而是在姐妹染色体分辨率和丝粒组织中起更复杂的作用。我们还证明了存在具有重叠成分的两个冷凝蛋白复合物，但在有丝分裂和X染色体基因调节中的功能不同。此后，很明显，人类细胞还包含两个冷凝蛋白（冷凝蛋白I和II），这都是有丝分裂所必需的，但具有明显的染色体定位，功能和调节。关于冷凝剂的重要问题包括确定每个复合物执行的精确函数，这些功能在多大程度上是唯一的或多余的，以及如何通过细胞周期和开发来差异地调节这些功能。在初步研究中，我们确定了其他冷凝蛋白I和II亚基，提供了用于染色体分离中功能的冷凝蛋白I的证据，并确定了可能将冷凝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物的组成和数量并识别其相关蛋白质。 2）确定不同冷凝蛋白复合物在有丝分裂，减数分裂和基因调节中的不同功能。 3）确定如何通过细胞周期激酶调节冷凝蛋白。这项研究将提供有关细胞如何确保细胞分裂过程中遗传物质准确分布的洞察力，并避免在流产和实体瘤中经常观察到的染色体误差。