Condensin and Chromosome Segregation in C. elegans

线虫中的凝缩蛋白和染色体分离

• 批准号: 7430389
• 负责人: KIRSTEN A HAGSTROM
• 金额: $ 30.22万
• 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/7430389
• 关键词: ATP Hydrolysis; Animal Model; Binding; Caenorhabditis elegans; Cell Cycle; Cell Death; Cell division; Cells; Centromere; Chromatin; Chromosome Condensation; Chromosome Pairing; Chromosome Segregation; Chromosome Structures; Chromosomes; Co-Immunoprecipitations; Comparative Study; Complex; Congenital Abnormality; DNA; Dependency; Development; Ensure; Environmental Wind; Event; Failure; Gene Expression Regulation; Genes; Genetic Materials; Genetic Recombination; Genome; Genome Stability; Glutathione S-Transferase; Goals; Health; Heterochromatin; Human; Immunoprecipitation; In Vitro; Label; Lead; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Meiosis; Microscopy; Mitosis; Mitotic; Mitotic Chromosome; Molecular; Morphology; Mutation; Numbers; Phosphorylation Site; Phosphotransferases; Physical condensation; Play; Process; Proteins; RNA Interference; Regulation; Research; Resolution; Role; Score; Sister Chromatid; Solid Neoplasm; Specificity; Spontaneous abortion; Staging; Sucrose; Synapses; System; Testing; Thinking; Transgenes; X Chromosome; Yeasts; aurora B kinase; base; condensin; daughter cell; feeding; in vivo; insight; male; mutant; paralogous gene; research study; segregation; time use; 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(申请人提供)：在每个细胞分裂过程中，基因组必须准确地复制并将一套完整的染色体分离到每个子细胞中。染色体分离的失败会对人类健康造成严重后果，因为产生染色体数量不适当的细胞可能会导致细胞死亡、出生缺陷或癌症。我们研究的长期目标是确定控制染色体分离的分子机制和机制，以确保基因组的稳定性。这项建议侧重于凝集素蛋白复合体，保守的染色体组织和分离的关键调节因子。凝聚素在减数分裂和有丝分裂染色体分离之前结合和重新配置它们，并被认为是通过使用ATP水解物将DNA缠绕成大环来做到这一点。我们试图了解多个凝聚素复合体的功能和组成，它们并不像最初想象的那么简单。利用模式生物秀丽线虫，我们证明了凝集素不是一个简单的紧凑因子，而是在姐妹染色单体分辨和着丝粒组织中发挥着更复杂的作用。我们还证明了存在两个成分重叠但在有丝分裂和X染色体基因调控中具有不同功能的凝集素复合体。人类细胞也含有两种凝集素(凝集素I和凝聚素II)，这两种凝集素都是有丝分裂所必需的，但具有不同的染色体定位、功能和调节。有关凝聚素的重要未解问题包括确定每个复合体执行的确切功能，这些功能在多大程度上是独特的或多余的，以及这些功能如何在细胞周期和发育过程中进行差异调节。在初步研究中，我们确定了额外的凝聚素I和II亚基，为凝聚素I在染色体分离中发挥作用提供了证据，并确定了可能将凝聚素功能与细胞周期联系在一起的激酶。我们建议：1)确定线虫复合体的组成和数量，并鉴定其相关蛋白。2)确定不同的凝集素复合体在有丝分裂、减数分裂和基因调控中的不同功能。3)确定凝聚素是如何受细胞周期蛋白激酶调控的。这项研究将为细胞如何确保细胞分裂期间遗传物质的准确分布提供洞察，并避免在流产和实体瘤中经常观察到的染色体错误。