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

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.

项目概要 有丝分裂期间着丝粒凝聚力的保护和随后的去保护对于 防止染色体错误分离并保持基因组稳定性。 着丝粒内聚力由内着丝粒（两个姐妹着丝粒之间的位置）定义 Shugoshin (Sgo1) 蛋白的安装和去除，但控制该蛋白的潜在机制 Sgo1 在内部着丝粒的定位鲜为人知，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 该提案的目的是确定控制疾病的基本机制。 我们之前发现 Bub1 依赖性 RNA 聚合酶 II 的内着丝粒定位。 转录涉及在最初着丝粒招募后将 Sgo1 安装到内部着丝粒。 初步数据表明，细胞PP2A抑制剂SET可以直接结合Sgo1并抑制 Sgo1-cohesin 相互作用。核心假设是 Bub1 依赖性主动转录 RNAP。 （RNA 聚合酶）II 在有丝分裂早期结合 Sgo1 并将其递送至内部着丝粒，并且 SET 和/或 PP1（磷酸酶 1）在中期到后期的转变过程中从内部着丝粒中去除 Sgo1。 这项研究的基本原理是对着丝粒凝聚力调控的探索是 在强有力的初步数据的指导下，这一假设对于理解其在基因组稳定性中的作用至关重要。 测试所追求的两个具体目标：1）确定着丝粒转录的功能和调控 有丝分裂中；和 2) 确定着丝粒内聚力是如何去保护的。 确定 Bub1-H2A-pT120 是否维持转录促进表观遗传组蛋白标记，以促进 转录，并且如果延长 RNAP II 结合并将 Sgo1 传递到着丝粒粘连蛋白，从而使 在第二个目标下，我们将确定 SET 和/或 PP1 是否从内部删除 Sgo1。 通过破坏 Sgo1-cohein 相互作用来实现中期到后期转变的着丝粒。 申请者认为，拟议的研究具有创新性，因为它通过以下方式改变了现状 揭示了决定着丝粒时间控制的全新且重要的机制 这项研究也很重要，因为它有望纵向推进和扩展。 了解正确染色体分离所必需的分子机制 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。