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Structure and Function of a Eukaryotic Centromere

真核着丝粒的结构和功能

基本信息

批准号：
10432882
负责人：
Kerry S Bloom
金额：
$ 52.89万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-07-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10432882
关键词：
Address Anaphase Aneuploidy Appearance Behavior Binding Sites Biochemical Biochemical Process Biophysical Process Cell Nucleolus Cell division Cells Centromere Characteristics Chromatin Chromatin Loop Chromosome Breakage Chromosome Segregation Chromosome Structures Chromosomes Complex DNA DNA Sequence Defect Engineering Ensure Entropy Equus caballus Fission Yeast Flowers Fluorescent Probes Foundations Goals Human Kinetochores Laboratories Lead Length Link Mathematics Mechanics Mediating Metabolism Metaphase Microtubules Mitosis Mitotic spindle Modeling Moths Nonhomologous DNA End Joining Nuclear Nucleoplasm Pathway interactions Peptides Phase Phylogeny Physics Plants Plus End of the Microtubule Polymers Property Protein Complex Subunit Proteins Radial Series Signal Transduction Sister Sister Chromatid Site Solvents Structure System Temperature Testing Time Yeasts arm base bioimaging biophysical properties cancer cell cohesin cohesion computerized tools condensin density experience fluorescence imaging fly forest homologous recombination in silico innovation insight microscopic imaging monomer repaired segregation self assembly simulation small molecule theories

项目摘要

Project Summary Goals: The centromere serves as the binding site for the kinetochore and is essential for the faithful segregation of chromosomes throughout cell division. The point centromere in yeast is encoded by a ~115 bp specific DNA sequence, whereas regional centromeres span 6-10 kbp in fission yeast to 5-10 Mbp in human. Despite the apparent diversity in centromere organization, the distance between sister kinetochores in metaphase ranges from 800 nm to 1,000 nm in yeast, worms, flies, flower moths, plants, horses and human. Understanding the physical structure of centromere chromatin (pericentromere in yeast, defined as the chromatin between sister kinetochores) will provide fundamental insights how centromere DNA is organized into a stiff spring that resists microtubule pulling forces during mitosis. Approach: Our laboratory develops computational tools to interrogate the structure and dynamics of hundreds of kilobase pairs of pericentromeric DNA. Together with experimentally obtained images of fluorescent probes of pericentromeric structure (e.g. pericentromere DNA, cohesin, condensin) we make quantitative comparisons between simulations and experimental results through transformation of in silico models into microscope images (model convolution). We will test the proposal that the mechanism for building tension between sister kinetochores is a chromatin bottlebrush organized by the loop-extruding proteins condensin and cohesin. The bottlebrush provides a biophysical mechanism that transforms pericentromeric chromatin into a spring due to the steric repulsion between radial loops. The bottlebrush as an organizing principle for chromosome organization has emerged from multiple approaches in the field. We will leverage the powerful features of chromosome engineering in yeast to explore the consequences of reducing the number of centromeres, and exploit synthetic bottlebrushes and statistical physics of polymer models to reveal basic principles linking bottlebrush structure to the functional readout of force/tension. Innovation: We will combine our experience in chromosome engineering and advanced bioimaging in yeast with the expertise of collaborators in statistical physics and applied math (Forest UNC-CH) and synthetic bio-inspired materials (Freeman UNC-CH). Testing our hypotheses will elucidate important information about the organization and function of centromeres, potentially providing a paradigm shifting foundation for the remarkable conservation of distance between sister kinetochores throughout phylogeny.

项目摘要目的：着丝粒作为着丝粒的结合位点，对染色体的功能至关重要。在整个细胞分裂过程中染色体的忠实分离。酵母中的点着丝粒是由约115 bp的特异性DNA序列编码，而区域着丝粒跨越6-10 kbp，裂殖酵母在人类中的5-10 Mbp。尽管着丝粒组织有明显的多样性，中期姐妹动粒之间的距离为800 nm至1，000 nm，酵母、蠕虫、苍蝇、花蛾、植物、马和人类。理解物理着丝粒染色质的结构（酵母中的近着丝粒，定义为姐妹动粒）将提供基本的见解如何着丝粒DNA组织成一个在有丝分裂过程中抵抗微管拉力的刚性弹簧。方法：我们的实验室开发了计算工具来询问结构，近着丝粒DNA的数百对酶的动力学。在实验上，获得了着丝粒周围结构的荧光探针（例如着丝粒周围DNA， cohesin，condensin），我们进行定量比较模拟和实验通过将计算机模型转换为显微镜图像（模型卷积）获得结果。我们将检验这样一种假设，即在姐妹动粒之间建立紧张关系的机制是由环挤压蛋白质凝聚素和粘着素组织的染色质瓶刷。的瓶刷提供了一种生物物理机制，将着丝粒周围染色质转化为由于径向环之间的空间排斥而产生的弹簧。瓶刷作为一种组织染色体组织的原理已经从该领域的多种方法中出现。我们将利用酵母染色体工程的强大功能来探索减少着丝粒数量的后果，并利用合成瓶刷，聚合物模型的统计物理学，以揭示瓶刷结构与力/张力的功能读数。创新：我们将联合收割机结合我们在染色体工程方面的经验和先进的利用统计物理学和应用数学方面的合作者的专业知识，（Forest UNC-CH）和合成生物启发材料（Freeman UNC-CH）。测试我们假设将阐明有关组织和功能的重要信息，着丝粒，潜在地提供了一个范式转换的基础，在整个生殖过程中保持姐妹动粒之间的距离。