Timing Control of Centromeric Cohesion through Centromere-localized Sgo1

通过着丝粒定位的 Sgo1 控制着丝粒凝聚的时间

• 批准号: 10249286
• 负责人: Hong Liu
• 金额: $ 31.92万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249286
• 关键词: Anaphase; Aneuploidy; Binding; Centromere; Chromosomal Stability; Chromosome Arm; Chromosome Segregation; Chromosomes; Complex; DNA Polymerase II; Data; Development; Disease; Epigenetic Process; Excision; Future; Genetic Transcription; Genome Stability; Goals; Histone H2A; Histones; Human; Kinetochores; Knowledge; Malignant Neoplasms; Mediating; Metaphase; Mission; Mitosis; Mitotic; Molecular; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Public Health; RNA; RNA Polymerase II; Regulation; Research; Role; S Phase; SET gene; Sister; Sister Chromatid; Small Interfering RNA; Suggestion; Testing; United States National Institutes of Health; Work; cancer cell; cancer therapy; chromosome missegregation; cohesin; cohesion; inhibitor/antagonist; innovation; novel; preservation; prevent; recruit; tumorigenesis; Anaphase; Aneuploidy; Binding; Centromere; Chromosomal Stability; Chromosome Arm; Chromosome Segregation; Chromosomes; Complex; DNA Polymerase II; Data; Development; Disease; Epigenetic Process; Excision; Future; Genetic Transcription; Genome Stability; Goals; Histone H2A; Histones; Human; Kinetochores; Knowledge; Malignant Neoplasms; Mediating; Metaphase; Mission; Mitosis; Mitotic; Molecular; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Public Health; RNA; RNA Polymerase II; Regulation; Research; Role; S Phase; SET gene; Sister; Sister Chromatid; Small Interfering RNA; Suggestion; Testing; United States National Institutes of Health; Work; cancer cell; cancer therapy; chromosome missegregation; cohesin; cohesion; inhibitor/antagonist; innovation; novel; preservation; prevent; recruit; tumorigenesis

Project Summary Protection and subsequent de-protection of centromeric cohesion during mitosis is essential for preventing chromosome missegregation and preserving genomic stability. This timing control of centromeric cohesion is defined by the inner-centromeric (the place between two sister centromeres) installment and removal of Shugoshin (Sgo1) proteins, but the underlying mechanisms that control the Sgo1 localization at inner centromeres are little known. The long-term goal is to understand the molecular mechanisms of chromosome segregation and their relationships with aneuploidy-driven processes and diseases. The objective of this proposal is to determine the essential mechanisms controlling the inner-centromere localization of Sgo1. We previously found that Bub1-dependent RNA polymerase II transcription is involved in installing Sgo1 at inner centromeres after initial kinetochore recruitment. Our preliminary data show that SET, a cellular PP2A inhibitor, can directly bind Sgo1 and inhibit the Sgo1-cohesin interaction. The central hypothesis is that Bub1-dependent actively-transcribing RNAP (RNA polymerase) II binds and delivers Sgo1 to inner centromeres at early mitosis, and that SET and/or PP1 (phosphatase 1) removes Sgo1 from inner centromeres at metaphase-to-anaphase transition. The rationale underlying this research is that the exploration of the regulation of centromeric cohesion is critical to understand its role in genome stability. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the function and regulation of centromeric transcription in mitosis; and 2) Determine how centromeric cohesion is de-protected. Under the first aim, we will determine if Bub1-H2A-pT120 maintains the transcription-promoting epigenetic histone marks to facilitate transcription, and if elongating RNAP II binds and delivers Sgo1 to centromeric cohesin, thus enabling Sgo1 function. Under the second aim, we will determine if SET and/or PP1 removes Sgo1 from inner centromeres at metaphase-to-anaphase transition by disrupting the Sgo1-cohein interaction. The proposed research is innovative, in the application’s opinion, because it departs the status quo by revealing totally novel and important mechanisms that determine the timing control of centromeric cohesion. This research is also significant, because it is expected to vertically advance and expand understanding of the molecular mechanisms that are essential for proper chromosome segregation and prevent aneuploidy. Ultimately, such knowledge will help identify potential targets for future development of new anti-cancer therapy.

项目摘要 在有丝分裂过程中的丝粒内凝聚的保护和随后的防止保护是至关重要的 防止染色体错误地进行分析并保留基因组稳定性。这个定时控制 丝粒内内中心粒子（两个姐妹centromeres之间的位置）定义了丝粒内聚力 安装和去除Shugoshin（SGO1）蛋白质，但是控制该蛋白的基本机制 SGO1在内侧丝粒处的定位鲜为人知。长期目标是了解分子 染色体分离的机制及其与非整倍性驱动过程的关系 疾病。该提议的目的是确定控制的基本机制 SGO1的内中心粒子定位。我们先前发现BUB1依赖性RNA聚合酶II 初始动物学募集后，转录参与在内侧丝粒上安装SGO1。我们的 初步数据表明，SET是一种细胞PP2A抑制剂，可以直接结合SGO1并抑制 SGO1-粘蛋白相互作用。中心假设是BUB1依赖性主动转录RNAP （RNA聚合酶）II在早期有丝分裂时结合并传递SGO1与内侧粒子，并将其设置和/或 pp1（磷酸酶1）从中期向上迁移的内侧粒子中去除SGO1。这 这项研究的基本原理是探索着丝粒凝聚力的调节是 了解其在基因组稳定性中的作用至关重要。在强大的初步数据的指导下，该假设将是 通过追求两个具体目的测试：1）确定丝粒转录的功能和调节 有丝分裂； 2）确定丝粒凝聚力如何去保护。在第一个目标下，我们将 确定BUB1-H2A-PT120是否保持转录促进表观遗传组蛋白标记以促进 转录，如果拉长RNAP II结合并将SGO1递送至丝粒粘着素，从而使 SGO1功能。在第二个目标下，我们将确定设置和/或PP1是否从内部删除SGO1 通过破坏SGO1-COHEIN相互作用，中期到方向体转变处的中心粒。这 该应用程序认为，拟议的研究具有创新性，因为它离开了现状 揭示完全新颖而重要的机制，这些机制决定了中心的时间控制 凝聚。这项研究也很重要，因为它有望垂直提高和扩展 了解对于适当的染色体隔离至关重要的分子机制和 防止非整倍性。最终，这些知识将有助于确定未来发展的潜在目标 新的抗癌疗法。