Structure and Pharmacologic Modulation of the Mitotic Chromosome's Central Axis

有丝分裂染色体中轴的结构和药理学调节

• 批准号: 10704101
• 负责人: Andrew J. Beel
• 金额: $ 39.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704101
• 关键词: 3-Dimensional; Acceleration; Affinity; Architecture; Biology; Cellular biology; Chemicals; Chromatin; Chromatin Loop; Chromosomal Instability; Chromosome Condensation; Chromosomes; Clinical; Communities; Cryo-electron tomography; Cryoelectron Microscopy; Development; Disease; Electron Microscope; Ensure; Environment; Equipment; Eukaryota; Event; Evolution; Faculty; Filament; Foundations; Funding; Genetic Transcription; Genome; Genomic Instability; Genomics; Goals; Health; Hematologic Neoplasms; Human; Hydrogels; Institution; Interphase; Investigation; Kinetochores; Knowledge acquisition; Laboratories; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Mentors; Mentorship; Metaphase; Methods; Mitotic; Mitotic Chromosome; Molecular; Nature; Neoplastic Processes; Pathway interactions; Phase Transition; Physical condensation; Play; Positioning Attribute; Procedures; Protocols documentation; RNA Polymerase II; Research; Research Personnel; Resolution; Role; Scientist; Shapes; Site; Societies; Solid; Source; Structure; Therapeutic; Training; Uncertainty; United States National Academy of Sciences; Work; cancer cell; condensin; equipment acquisition; experience; foot; genetic information; high risk; immune clearance; inhibitor; invention; member; next generation sequencing; novel; organizational structure; pharmacologic; professor; scaffold; sequencing platform; small molecule; small molecule inhibitor; structural biology; success; targeted cancer therapy; tenure track; theories; therapy resistant; tool

Project Summary Mitotic chromosome formation is essential for the dissemination of genetic information in eukaryotes. The conversion of dispersed interphase chromatin into the iconic, X-shaped metaphase chromosome involves three principal events: the formation of a central axis (the chromosomal “scaffold”), lengthwise contraction, and condensation. Plausible theories have been advanced to explain the latter two events, with contraction occurring through the extrusion of chromatin loops and condensation occurring through a volume phase transition of the chromosomal material. In contrast, little is known about the formation of the mitotic scaffold, and its very existence has been the source of considerable controversy. Direct evidence for the scaffold's existence has recently come from the observation of a central filament in native mitotic chromosomes subjected to controlled expansion ex vivo. This filament could be liberated, intact, from its chromosomal confines by careful nucleolysis, providing a basis for further study. This proposal aims to elucidate basic principles of the mitotic chromosome scaffold, including its molecular composition (Aim 1), its three-dimensional architecture (Aim 2), and its interactions with the chromatin enveloping it (Aims 1 and 2). The information obtained will provide a global view of the core of the mitotic chromosome, explaining how its components assemble into a structure of mesoscopic proportions and how this structure organizes the genome in a manner ensuring its faithful and efficient distribution. The acquired knowledge will enable more detailed investigations into the mechanisms governing scaffold assembly and disassembly and the nature of its interactions with other cellular components (e.g., chromatin, kinetochores). This proposal also seeks to develop chemical modulators of scaffold assembly (Aim 3). As the scaffold and its constituents are increasingly understood to play important roles in human health and disease, such tools will not only enable further research on the scaffold but will also allow for its pharmacological manipulation in clinical contexts. Dysregulation of scaffold components such as the condensins, for instance, has been implicated in a growing number of malignancies, where they contribute to a particular form of genome instability known as chromosome instability. Genome instability is a key factor in the evolution of cancer cells, facilitating their escape from immune clearance and their acquisition of therapeutic resistance. By suppressing a pathway leading to chromosome instability, modulators of condensins (and other scaffold components) may act to limit the evolutionary potential of cancer cells.

项目概要 有丝分裂染色体的形成对于真核生物遗传信息的传播至关重要。 分散的间期染色质转化为标志性的 X 形中期染色体 涉及三个主要事件：中心轴（染色体“支架”）的形成、纵向 收缩、凝结。人们提出了合理的理论来解释后两个事件， 通过染色质环的挤压发生收缩，通过染色质环发生凝结 染色体材料的体积相变。相比之下，人们对它的形成知之甚少。 有丝分裂支架的存在及其存在本身就引起了相当大的争议。直接的 支架存在的证据最近来自于对中心细丝的观察 天然有丝分裂染色体在体外进行受控扩张。这根细丝可以被释放， 通过仔细的核解作用从其染色体范围中获得完整的结果，为进一步研究提供了基础。 该提案旨在阐明有丝分裂染色体支架的基本原理，包括其 分子组成（目标 1）、其三维结构（目标 2）及其与 包围它的染色质（目标 1 和 2）。获得的信息将提供全局视图 有丝分裂染色体的核心，解释其组件如何组装成介观比例的结构，以及该结构如何以确保其忠实和可靠的方式组织基因组 高效分配。所获得的知识将有助于更详细地研究支架组装和拆卸的机制及其与其他细胞相互作用的性质 成分（例如染色质、着丝粒）。 该提案还寻求开发支架组装的化学调节剂（目标 3）。作为 人们越来越认识到支架及其成分在人类健康和 疾病，这些工具不仅可以对支架进行进一步的研究，而且还可以在临床环境中对其进行药理学操作。例如，支架成分（例如凝缩蛋白）的失调与越来越多的恶性肿瘤有关，它们在其中发挥着重要作用 一种特殊形式的基因组不稳定性，称为染色体不稳定性。基因组不稳定是关键 癌细胞进化的因素，促进它们逃避免疫清除并获得治疗耐药性。通过抑制导致染色体不稳定的途径，调节剂 凝缩蛋白（和其他支架成分）可能会限制癌症的进化潜力 细胞。