Regulation of Centromeric Chromatin

着丝粒染色质的调控

• 批准号: 7990425
• 负责人: Susan Biggins
• 金额: $ 30.4万
• 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 2012-02-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990425
• 关键词: Address; Aneuploidy; Area; Binding; Biochemical; Biochemical Genetics; Cell Cycle; Cell division; Cells; Centromere; Chromatin; Chromatin Structure; Chromosome Segregation; Chromosomes; Congenital Abnormality; DNA Sequence; Data; Deposition; Ensure; Epigenetic Process; Euchromatin; Eukaryota; Foundations; Generations; Genetic; Genetic Screening; Genome; Genome Stability; Genomic Instability; Goals; Histone H3; Histones; In Vitro; Inherited; Kinetochores; Lead; Maintenance; Malignant Neoplasms; Mediating; Methods; Mitosis; Modeling; Molecular; Nucleosomes; Organism; Pattern; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Regulation; Relative (related person); Saccharomycetales; Specific qualifier value; Testing; Time; Variant; base; daughter cell; histone modification; human disease; in vivo; meetings; mutant; prevent; protein structure; 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 all tumors and many birth defects. We are studying chromosome segregation in budding yeast because it is amenable to both genetic and biochemical analyses, and the mechanism of chromosome segregation is fundamentally conserved. Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA sequences and mediate attachment to the spindle. Because centromeric DNA sequences are not conserved, centromere identity is propagated by an epigenetic mechanism. A hallmark of epigenetic regulation is a specialized chromatin structure that is characterized by the presence of histone variants and unique post-translational modifications to histones. Consistent with this, all eukaryotic centromeres contain an essential histone H3 variant (CenH3) that is required for kinetochore assembly and is likely to be the epigenetic mark that specifies centromere identity. In addition, the H2A.Z histone variant localizes to pericentromeric and centromeric chromatin in a number of organisms, and centromeres contain a distinct histone modification pattern relative to euchromatin. Although a specialized chromatin structure is essential for centromere identity and function, the mechanisms that assemble and maintain centromeric chromatin have not been elucidated. We will therefore take complementary biochemical and genetic approaches to identify factors that deposit CenH3 at centromeres. In addition, we will identify the mechanisms that maintain CenH3 at the centromere and prevent it from localizing to euchromatin. Finally, we have developed a method to enrich for histones associated with centromeres that will allows us to identify centromere-specific histone modifications that are important for chromosome segregation. Taken together, these studies will lead to a better understanding of chromosome segregation and the maintenance of centromere identity and genomic stability in all eukaryotes. Project Narrative All cells must inherit the right number of chromosomes every time they divide because the wrong number of chromosomes is a hallmark of all cancers and a number of birth defects. 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所有生物体的生成和生存至关重要。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体，这是所有肿瘤和许多出生缺陷的标志。我们正在研究芽殖酵母中的染色体分离，因为它适合于遗传和生化分析，并且染色体分离的机制基本上是保守的。染色体利用它们的动粒分离，动粒是组装在着丝粒DNA序列上并介导与纺锤体连接的专门蛋白质结构。由于着丝粒DNA序列不保守，因此着丝粒同一性通过表观遗传机制传播。表观遗传调控的标志是特化的染色质结构，其特征在于组蛋白变体的存在和对组蛋白的独特翻译后修饰。与此相一致，所有真核着丝粒都含有一个必需的组蛋白H3变体（CenH3），该变体是着丝粒组装所需的，并且可能是指定着丝粒身份的表观遗传标记。此外，H2A.Z组蛋白变体在许多生物体中定位于近着丝粒和着丝粒染色质，并且着丝粒相对于常染色质含有不同的组蛋白修饰模式。虽然一个专门的染色质结构是必不可少的着丝粒的身份和功能，组装和维持着丝粒染色质的机制尚未阐明。因此，我们将采取互补的生物化学和遗传学方法，以确定存款CenH3在着丝粒的因素。此外，我们将确定将CenH3维持在着丝粒并防止其定位于常染色质的机制。最后，我们已经开发了一种方法来富集与着丝粒相关的组蛋白，这将使我们能够识别对染色体分离很重要的着丝粒特异性组蛋白修饰。总之，这些研究将导致更好地了解染色体分离和维护着丝粒的身份和基因组的稳定性在所有真核生物。 所有细胞在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所有癌症和一些出生缺陷的标志。因此，我们正在研究染色体在分裂时分配给子细胞的过程，以了解许多人类疾病的基础。