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.

项目概要 同源染色体进入减数分裂时彼此不相连，但它们通过 这些连接有助于同源染色体彼此远离。 减数分裂 I. 当同源着丝粒附着在同源着丝粒上时，这些连接传递张力 来自纺锤体相对两侧的微管（双向）。 因此，交换失败可能导致减数分裂错误和非整倍体配子。 减数分裂前期的同源着丝粒配对（CEN-pairing）是最近发现的一种保守的 在酵母中，CEN 配对有助于伴侣染色体随后在后期 I 分离。 正确地，即使他们没有经历交叉 CEN 配对促进的机制。 虽然交叉形成已被研究了数十年，但人们知之甚少。 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。 1 我们测试了这样的假设：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。 具有或不具有转基因 CEN 配对的染色体对的减数分裂行为 在目标 2 中，我们将测试 Aim 3 将探索 CEN 配对期间形成的连接由粘连蛋白介导的假设。 着丝粒-着丝粒连接帮助伴侣染色体变成双向的机制 我们将直接测量着丝粒与着丝粒连接的弹簧特性。 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 此外，这些实验将检验以下假设： 着丝粒-着丝粒连接对于提高染色体对的分离保真度非常重要 通过交叉连接，单独使用交叉无法有效地创建张力传递桥，因为这对 该项目中的实验将共同阐明一些附着在微管上的原因。 交叉确实（有些不能）有效地确保减数分裂中染色体的高保真度分离，并且会 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，或者可以单独起作用 当交叉失败时。