Organization and Regulation of Eukaryotic Centromeres

真核着丝粒的组织和调控

• 批准号: 6704973
• 负责人: BETH A SULLIVAN
• 金额: $ 30.69万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704973
• 关键词: Drosophilidae; aneuploidy; artificial chromosomes; cell cycle; centromere; chromatin immunoprecipitation; chromosomes; eukaryote; fluorescent in situ hybridization; fungal genetics; genetic mapping; heterochromatin; histones; immunofluorescence technique; methylation; microscopy; nucleosomes; protein localization; yeasts

DESCRIPTION (provided by applicant): Chromosome inheritance ensures transmission of genetic information. Abnormal chromosome segregation severely affects the health and viability of all cells and organisms. Errors in chromosome inheritance lead to chromosome abnormalities (aneuploidy) that cause many birth defects, such as Down Syndrome and miscarriages, and are the hallmarks of almost all types of cancers. The centromere, a complex of DNA and proteins, is central to the chromosome inheritance process and contributes to formation of the kinetochore, heterochromatin and sister chromatid cohesion. Defects in centromere functions lead to aneuploidy or tumor formation in yeast, flies and mice. CENP-A, a conserved H3-1ike histone that replaces H3 in centromeric nucleosomes, is the structural and functional foundation of the kinetochore and adjacent centromeric region. We have shown that kinetochore chromatin is uniquely arranged as interspersed domains of CENP-A and H3 nucleosomes that promote a specialized cylindrical structure on metaphase chromosomes. This special structure is formed on divergent DNA sequences, and it is not known how centromeric chromatin is established and maintained, nor the structural and functional aspects if it is altered. The goal of this proposal is to apply an integrative, dual-system approach, using novel reagents and techniques that I have developed in my former lab, to test key organizational and functional aspects of centromeric chromatin in Drosophila and humans. We propose to investigate the roles of genomic structure and chromatin organization and dynamics in assembly and regulation of CENP-A chromatin, centromeric domains, and metaphase kinetochore structure.

描述（由申请人提供）：染色体遗传确保遗传信息的传播。异常的染色体分离严重影响所有细胞和生物的健康和生存能力。染色体遗传的错误导致染色体异常（非整倍）引起许多先天缺陷，例如唐氏综合症和流产，并且是几乎所有类型的癌症的标志。 CentRomere是DNA和蛋白质的复合物，是染色体遗传过程的核心，并有助于形成动力学，异染色质和姐妹染色单体。丝粒功能的缺陷导致酵母，苍蝇和小鼠的非整倍性或肿瘤形成。 CENP-A是一种替代丝粒核小体中H3的保守H3-1型组蛋白，是动元和邻近的centromeric区域的结构和功能基础。我们已经表明，动力学染色质是CENP-A和H3核小体的散布结构域的独特排列，这些结构域促进了中期染色体上专门的圆柱形结构。这种特殊的结构是在发散的DNA序列上形成的，尚不清楚如何建立和维持中心层染色质，也不知道如果改变了结构和功能方面。该提案的目的是使用我在以前的实验室中开发的新型试剂和技术应用一种综合的双层系统方法，以测试果蝇和人类中心层染色质的关键组织和功能方面。我们建议研究基因组结构和染色质组织的作用以及动态在CENP-A染色质，中心粒结构域和中期动物学结构中的调节。