Centromere Interactions and Meiotic Chromosome Segregation in Yeast

酵母着丝粒相互作用和减数分裂染色体分离

• 批准号: 10210732
• 负责人: DEAN S DAWSON
• 金额: $ 34.96万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210732
• 关键词: Anaphase; Aneuploidy; Behavior; Behavior monitoring; Cells; Centromere; Chromatin; Chromosome Pairing; Chromosome Segregation; Chromosomes; Congenital Abnormality; Distal; Distant; Drosophila genus; Ensure; Failure; Genetic Crossing Over; Germ Cells; Human; Infertility; Lead; Link; Measures; Mediating; Meiosis; Mental Retardation; Metaphase; Microscopy; Microtubule Stabilization; Microtubules; Modeling; Monitor; Mus; Positioning Attribute; Process; Prometaphase; Property; Prophase; Proteins; S Phase; Saccharomycetales; Side; Signal Pathway; Signal Transduction; Sister Chromatid; System; Testing; Work; Yeasts; biophysical techniques; chromosome movement; cohesin; cohesion; experience; experimental study; improved; live cell imaging; mutant; prevent; segregation

Project Summary Homologous chromosomes enter meiosis unconnected to each other, but they become linked by crossovers (exchanges). These linkages help the homologous chromosomes to move away from each other in meiosis I. The linkages transmit tension between the homologous centromeres when they become attached to microtubules from opposite sides of the spindle (bi-oriented). Tension stabilizes these microtubule attachments. Accordingly, failures in crossing-over can result in meiotic errors and aneuploid gametes. The pairing of homologous centromeres (CEN-pairing) in meiotic prophase, is a recently discovered, conserved phenomenon. In yeast, CEN-pairing helps the partner chromosomes, later, in anaphase I, to segregate properly, even if they have failed to experience a crossover. The mechanism by which CEN-pairing promotes segregation is unknown. While crossover formation has been investigated for decades, very little is known about how CEN-pairing promotes meiotic chromosome segregation. This is the focus of our proposal. In Aim 1 we test the hypothesis that the CEN-pairing allows the formation of centromere-centromere connections that improve the segregation fidelity of meiotic chromosome partners. We will use live cell imaging to monitor the meiotic behavior of chromosome pairs have or have not undergone CEN-pairing. In Aim 2 we will test the hypothesis that connections formed during CEN-pairing are mediated by cohesin proteins. Aim 3 will explore mechanism by which centromere-centromere connections help partner chromosomes become bi-oriented on the spindle. We will directly measure the spring-like properties of the centromere-to-centromere connections using bio-physical approaches and test whether partners with a centromere-centromere connection can use the tension-sensing signaling pathways. In addition, these experiments will test the hypothesis that centromere-centromere connections are important to improve the segregation fidelity of chromosome pairs linked by crossovers that alone would be ineffective in creating a tension-transmitting bridge as the pair attaches to microtubules. Together, the experiments in this project will elucidate the reasons that some crossovers do, and some don’t, effectively ensure high fidelity chromosome segregation in meiosis and will explain how the recently described process of centromere pairing can mediate the formation of a centromere- to-centromere connection between homologs that augments the functionality of crossovers, or can act alone when crossovers fail.

项目摘要 同源染色体进入减数分裂时彼此不相连，但它们通过 交叉(交易所)。这些连接帮助同源染色体在 减数分裂I.当同源着丝粒连接在一起时，连接传递着丝粒之间的张力 纺锤体两侧的微管(双向)。张力使这些微管稳定下来 附属品。因此，交换失败可能导致减数分裂错误和非整倍体配子。这个 减数分裂前期同源着丝粒配对(CEN配对)是最近发现的一种保守的 现象。在酵母中，CEN配对帮助配对染色体在后期I进行分离 正确地说，即使他们没有经历过跨界。CEN配对促进的机制 种族隔离是未知的。虽然对跨界形成的研究已经有几十年了，但人们对此知之甚少。 关于CEN配对如何促进减数分裂染色体分离。这是我们提案的重点。在AIM 1我们检验了CEN配对允许着丝粒-着丝粒连接形成的假设 提高减数分裂配对的分离保真度。我们将使用活细胞成像来监测 染色体对的减数分裂行为已经或没有经历过CEN配对。在目标2中，我们将测试 假设在CEN配对过程中形成的连接是由粘附素蛋白介导的。《目标3》将探索 着丝粒-着丝粒连接帮助配对染色体变得双向的机制 纺锤。我们将直接测量着丝粒到着丝粒连接的弹簧性质 使用生物物理方法并测试具有着丝粒-着丝粒连接的合作伙伴是否可以使用 张力感应信号通路。此外，这些实验将检验这一假设 着丝粒-着丝粒连接对提高染色体对的分离保真度很重要 通过交叉连接在一起，仅靠这种交叉将不能有效地创建作为对的张力传递桥 附着在微管上。总而言之，这个项目中的实验将阐明一些原因 杂交可以有效地确保减数分裂中的高保真染色体分离，而有些则不能。 解释最近描述的着丝粒配对过程如何调节着丝粒的形成- 同系物之间的着丝粒连接可以增强交叉的功能，或者可以单独起作用 当跨界失败时。