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: 10372222
• 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/10372222
• 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 交换（Exchange）。这些连接有助于同源染色体在染色体间相互分离， 减数分裂Ⅰ当它们连接到染色体上时，连接在同源着丝粒之间传递张力。 微管从纺锤体的相对侧（双向）。张力稳定了这些微管 附件的权限.因此，交换失败会导致减数分裂错误和非整倍体配子。的 同源着丝粒配对（CEN配对）是最近发现的，保守的， 现象在酵母中，CEN配对有助于配偶染色体在后期I分离 即使他们没有经历过交叉。CEN配对促进的机制 隔离是未知的。虽然交叉形成已经研究了几十年，但知之甚少 CEN配对如何促进减数分裂染色体分离。这是我们建议的重点。在Aim中 1我们检验了这样的假设，即CEN配对允许形成着丝粒-着丝粒连接， 提高减数分裂染色体伴侣的分离保真度。我们将使用活细胞成像来监测 染色体对的减数分裂行为是否经历了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由粘附蛋白介导。Aim 3将探索 着丝粒-着丝粒连接帮助伴侣染色体在染色体上双向取向的机制 主轴。我们将直接测量着丝粒到着丝粒连接的类似弹簧的性质 使用生物物理方法，并测试具有着丝粒-着丝粒连接的伴侣是否可以使用 张力感应信号通路。此外，这些实验将检验假设， 着丝粒-着丝粒连接对提高染色体对的分离保真度很重要 由交叉连接，单独在创建一个张力传递桥梁时是无效的， 附着在微管上总之，这个项目中的实验将阐明一些原因， 杂交确实有效地确保了减数分裂中染色体的高保真分离， 解释最近描述的着丝粒配对过程如何介导着丝粒的形成- 同源物之间的着丝粒连接，增强了交叉的功能，或可以单独起作用 当跨界失败时。