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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结