Control of Chromosome Segregation by DNA Topoisomerase II

DNA 拓扑异构酶 II 控制染色体分离

• 批准号: 10324569
• 负责人: DUNCAN J. CLARKE
• 金额: $ 29.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324569
• 关键词: Advanced Development; Anaphase; Aneuploidy; Area; Binding; Biochemical; C-terminal; Cancer Etiology; Catalytic Domain; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Chromatids; Chromosome Segregation; Chromosomes; Complex; Congenital Abnormality; DNA; DNA Damage; DNA biosynthesis; Data; Defect; Drug Targeting; Ensure; Enzymes; Failure; Feeds; Functional disorder; Genetic; Genome; Genomic Instability; Genomics; Human; Kinetochores; Light; Link; Locales; Malignant Neoplasms; Mechanics; Microtubules; Mitosis; Mitotic; Mitotic Cell Cycle; Mitotic Spindle Apparatus; Modeling; Molecular; Molecular Conformation; Monitor; Nuclear Pore Complex; Outcome Study; Pathway interactions; Phase; Population; Positioning Attribute; Process; Production; Reaction; Regulation; Role; SHPS-1 protein; Signal Transduction; Signaling Molecule; Signaling Protein; Sister Chromatid; Site; Therapeutic; Topoisomerase II; Topoisomerase II inhibition; Translational Research; Yeasts; biochemical tools; cancer therapy; daughter cell; developmental disease; genetic approach; insight; mutant; novel; protein protein interaction; public health relevance; recruit; response; scaffold; segregation; therapeutic target; tool; transmission process; treatment strategy

Abstract Chromosome segregation errors result in aneuploidy which causes birth defects and cancer. We have defined a new mitotic Topo II-responsive control (TRC) in yeast that delays the cell cycle when Topo II activity is insufficient for accurate chromosome segregation. This TRC mechanism is conserved in human cells, but has not been extensively studied. Activation of the TRC is triggered by defects in the strand passage reaction of Topo II, when the enzyme transits too slowly through its structural conformations. TRC activation also requires the catalytically inert C-terminal domain of Topo II, which contains novel protein- protein interaction motifs that bind to TRC signaling proteins. The central model is that aberrant strand passage may structurally transfer from the catalytic core of Topo II to the C-terminal domain which functions as a signal-generating scaffold to halt the cell cycle. The conservation between the human and yeast TRC responses provides unique opportunities to identify the TRC components and to reveal the mechanism of TRC activation. We aim to determine the cellular/genomic sites of TRC activation, the signaling molecules involved and the mechanism of TRC activation by the C-terminal domain of Topo II. The results of these studies will impact opportunities for translational research because we will identify new potential therapeutic targets. Our findings will also impact the use of widely prescribed therapeutic drugs that target Topo II because we will gain mechanistic insight into cellular responses to Topo II inhibition. The preliminary data and newly developed experimental tools place us in a unique position to determine the conserved mechanism of this scarcely studied mitotic control.

摘要 染色体分离错误会导致非整倍体，从而导致出生缺陷和癌症。我们有 在酵母中定义了一种新的有丝分裂Topo II反应控制(TRC)，当Topo II 活性不足以进行准确的染色体分离。这种TRC机制在人类中是保守的 细胞，但尚未得到广泛研究。TRC的激活是由链中的缺陷触发的 TOPO II的传递反应，当酶在其结构构象中转换得太慢时。TRC 激活还需要Topo II的催化惰性C末端结构域，该结构域包含新的蛋白质- 与TRC信号蛋白结合的蛋白质相互作用基序。中心模型是异常链 通道可以从Topo II的催化核心结构转移到具有功能的C-末端结构域 作为停止细胞周期的信号产生支架。人与酵母TRC基因的保守性 反应提供了独特的机会，以确定TRC组件和揭示机制 激活TRC。我们的目标是确定TRC激活的细胞/基因组位置，即信号分子 以及TOPO II的C-末端结构域激活TRC的机制。 研究将影响转化研究的机会，因为我们将确定新的潜在治疗方法 目标。我们的发现还将影响针对Topo II的广泛处方治疗药物的使用 因为我们将获得对Topo II抑制的细胞反应的机械性洞察。初步数据 新开发的实验工具使我们处于一个独特的位置来确定保守的 这一机制几乎没有研究过有丝分裂的控制。