Regulation of Centromeric Chromatin

着丝粒染色质的调控

• 批准号: 8237660
• 负责人: Susan Biggins
• 金额: $ 37.59万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237660
• 关键词: Address; Aneuploidy; Behavior; Binding Proteins; Biochemical; Biochemical Genetics; Biological Process; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell division; Cells; Centromere; Chromatin; Chromatin Structure; Chromosome Segregation; Chromosomes; Congenital Abnormality; Coupling; DNA; DNA Sequence; Data; Defect; Deposition; Development; Disease; Ensure; Epigenetic Process; Euchromatin; Eukaryota; Excision; Foundations; Generations; Genetic; Genetic Transcription; Genome Stability; Genomic Instability; Genomics; Histone H3; Histones; Inherited; Kinetochores; Lead; Maintenance; Malignant Neoplasms; Mediating; Methods; Microtubules; Modeling; Monitor; Mutate; N-terminal; Nucleosomes; Organism; Post-Translational Protein Processing; Process; Protein Binding; Proteins; Proteolysis; Proteomics; Regulation; Role; Saccharomycetales; Sister; Structure; Tail; Techniques; Testing; Therapeutic Intervention; Time; Variant; Weight-Bearing state; Work; Yeasts; base; daughter cell; design; human disease; in vivo; insight; novel; prevent; protein structure; segregation; tumor

DESCRIPTION (provided by applicant): The flawless execution of cell division is essential to the generation and survival of all organisms. During every cell cycle, chromosomes must be accurately partitioned to daughter cells to prevent genomic instability and aneuploidy, a hallmark of many tumors and birth defects. Chromosomes segregate using their kinetochores, the specialized protein structures that assemble on centromeric DNA sequences and mediate attachment to microtubules. The foundation of all eukaryotic kinetochores is a conserved, inner centromere structure characterized by centromeric chromatin and its associated proteins. A hallmark of centromeric chromatin is Cenp-A, an essential histone H3 variant that epigenetically marks centromeres and is required for kinetochore assembly. The surrounding pericentromeric chromatin also makes various contributions to the fidelity of segregation. To fully understand the mechanisms that ensure accurate chromosome segregation, it is critical to elucidate outstanding questions about the functions and maintenance of centromeric and pericentromeric chromatin. This proposal will use purified kinetochores and a combination of biochemical, biophysical, proteomic and genomic approaches to address a number of outstanding questions about the contribution of centromeric chromatin to kinetochore function. 1) How do centromere-binding proteins contribute to the diverse functions of kinetochores? 2) How does pericentromeric chromatin regulate chromosome segregation? 3) What are the mechanisms that contribute to the exclusive localization of centromeres? The proposal will use budding yeast for these studies because they are amenable to biochemical, genetic and cytological studies, and the yeast kinetochore is the best characterized to date. Taken together, these studies of kinetochores and the underlying chromatin foundation in budding yeast will lead toward an understanding of the fundamental mechanisms of segregation in all eukaryotes. This work will not only elucidate important aspects about the process of segregation, but will aid in the design of better therapeutic interventions in the long-term. PUBLIC HEALTH RELEVANCE: All cells must inherit the right number of chromosomes every time they divide because the wrong number of chromosomes is a hallmark of cancer, birth defects, and other diseases related to problems in cell proliferation. We are therefore studying the process of chromosome partitioning to daughter cells when they divide to understand the basis for a number of human diseases.

描述（由申请人提供）：细胞分裂的完美执行对于所有生物体的产生和生存至关重要。在每个细胞周期中，染色体必须准确地分配给子细胞，以防止基因组不稳定和非整倍性，这是许多肿瘤和出生缺陷的标志。染色体利用动粒进行分离，动粒是在着丝粒 DNA 序列上组装并介导与微管附着的特殊蛋白质结构。所有真核动粒的基础是保守的内部着丝粒结构，其特征在于着丝粒染色质及其相关蛋白质。着丝粒染色质的一个标志是 Cenp-A，它是一种重要的组蛋白 H3 变体，可表观遗传地标记着丝粒，并且是动粒组装所必需的。周围的着丝粒周围染色质也对分离的保真度做出了各种贡献。为了充分了解确保染色体准确分离的机制，阐明有关着丝粒和着丝粒周围染色质的功能和维护的突出问题至关重要。该提案将使用纯化的着丝粒并结合生物化学、生物物理、蛋白质组学和基因组方法来解决有关着丝粒染色质对着丝粒功能的贡献的许多悬而未决的问题。 1) 着丝粒结合蛋白如何促进着丝粒的多种功能？ 2）着丝粒周围染色质如何调节染色体分离？ 3）有助于着丝粒独家定位的机制是什么？该提案将使用芽殖酵母进行这些研究，因为它们适合生化、遗传和细胞学研究，并且酵母着丝粒的特征是迄今为止最好的。总而言之，这些对出芽酵母中动粒和染色质基础的研究将有助于理解所有真核生物中分离的基本机制。这项工作不仅将阐明分离过程的重要方面，而且将有助于设计更好的长期治疗干预措施。 公共健康相关性：所有细胞每次分裂时都必须继承正确数量的染色体，因为错误数量的染色体是癌症、出生缺陷和其他与细胞增殖问题相关的疾病的标志。因此，我们正在研究子细胞分裂时染色体分配给子细胞的过程，以了解许多人类疾病的基础。