Regulation of Chromosome Cohesion during Cell Cycle Progression

细胞周期进展过程中染色体凝聚力的调节

• 批准号: 8506325
• 负责人: Susannah Rankin
• 金额: $ 30.24万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506325
• 关键词: Acetylation; Acetyltransferase; Address; Affect; Aneuploidy; Binding; Biochemical; Biological Assay; Bruck-de Lange syndrome; Cell Cycle Progression; Cell Nucleus; Cell division; Cellular biology; Chromatin; Chromosome Cohesion; Chromosome Segregation; Chromosomes; Complex; Congenital Abnormality; Cultured Cells; DNA; DNA Repair; DNA biosynthesis; Daughter; Development; Down Syndrome; Ensure; Enzymes; Event; Excision; Failure; Genes; Genomic Instability; Goals; Growth and Development function; Health; Heart; Human; Interphase; Lead; Maintenance; Malignant Neoplasms; Maternal Age; Mediating; Modeling; Molecular; Mutation; Process; Prophase; Proteins; Rana; Reaction; Recruitment Activity; Regulation; Relative (related person); Resolution; S Phase; Saccharomycetales; Series; Sister Chromatid; Spontaneous abortion; Substrate Specificity; System; Testing; Time; Turner' s Syndrome; Vertebrates; Work; advanced maternal age; age related; cohesin; cohesion; developmental disease; egg; improved; insight; programs; protein complex; protein function; public health relevance; research study; response; telophase; tumor

DESCRIPTION (provided by applicant): Following DNA replication, the two identical copies of each chromosome are held together until cell division by a process referred to as sister chromatid cohesion. Sister chromatid cohesion is essential for accurate chromosome segregation, repair of DNA damage, the maintenance of transcriptional programs, and normal development. Mutations in cohesion genes lead to birth defects and are associated with genomic instability associated with certain cancers. Failures in cohesion are thought to underlie the maternal age-related increase in aneuploid eggs, a major cause of birth defects and spontaneous abortion. Sister chromatid cohesion is mediated by a large protein complex called cohesin. The activity of this complex must be regulated to ensure that cohesin is laid down on chromatin and activated in a way that is integrated with DNA replication and cell cycle progression. This regulation is accomplished by the activities of several proteins that cooperate to regulate the stability of the cohesin-chromatin interaction. Here we propose a series of experiments to define both how these proteins, which we dub the "cohesin stability network", are regulated during DNA replication and in response to cell cycle progression. Using a combination of biochemical and cell biology approaches, including assays in cultured cells and frog egg extracts, we will define the functional interactions between the cohesin complex and this regulatory network. The results of these experiments will provide critical insight into the mechanism by which cohesion is established, maintained, and remodeled in vertebrate systems.

描述（由申请人提供）：在DNA复制之后，每条染色体的两个相同副本被结合在一起，直到通过称为姐妹染色单体内聚的过程进行细胞分裂。姐妹染色单体内聚对染色体的准确分离、DNA损伤的修复、转录程序的维持和正常发育至关重要。内聚基因的突变导致出生缺陷，并与与某些癌症相关的基因组不稳定性有关。凝聚力的失败被认为是母亲年龄相关的非整倍体卵子增加的基础，非整倍体卵子是出生缺陷和自然流产的主要原因。姐妹染色单体的内聚是由一种叫做内聚蛋白的大蛋白质复合物介导的。这个复合体的活性必须被调节，以确保内聚蛋白被放置在染色质上，并以一种与DNA复制和细胞周期进程相结合的方式被激活。这种调节是通过几种蛋白质的活动来完成的，这些蛋白质合作调节黏结蛋白-染色质相互作用的稳定性。在这里，我们提出了一系列的实验来定义这些蛋白质，我们称之为“内聚稳定性网络”，如何在DNA复制和细胞周期进程中受到调节。结合生物化学和细胞生物学的方法，包括在培养细胞和青蛙蛋提取物中进行的实验，我们将定义内聚蛋白复合物和这种调节网络之间的功能相互作用。这些实验的结果将对脊椎动物系统中内聚力建立、维持和重塑的机制提供关键的见解。