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

基本信息

批准号：
8876718
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8876718
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&apos s Syndrome Vertebrates Work advanced maternal age age related cohesin cohesion developmental disease differential expression egg improved insight programs protein complex protein function research study response telophase tumor

项目摘要

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）：DNA复制后，将每个染色体的两个相同的副本保留在一起，直到细胞分裂通过称为姐妹染色质被凝聚的过程。姐妹染色质被凝聚对于准确的染色体隔离，DNA损伤的修复，转录程序的维护以及正常发育至关重要。内聚力基因的突变导致出生缺陷，并与某些癌症相关的基因组不稳定性相关。凝聚力的失败被认为是母亲年龄相关的非整倍体卵的增加，这是出生缺陷和自发流产的主要原因。姐妹染色单体内聚会是由称为粘着素的大蛋白质复合物介导的。必须调节该复合物的活性，以确保粘质在染色质上放置并以与DNA复制和细胞周期进程的方式进行激活。该调节是通过几种蛋白质的活性来完成的，这些蛋白质合作调节了粘蛋白 - 染色质相互作用的稳定性。在这里，我们提出了一系列实验，以定义在DNA复制过程中调节这些蛋白质的“粘蛋白稳定网络”，并响应细胞周期进程。使用生化和细胞生物学方法的组合，包括在培养细胞和青蛙卵提取物中的测定，我们将定义粘蛋白复合物与该调节网络之间的功能相互作用。这些实验的结果将对在脊椎动物系统中建立，维护和重塑的内聚力的机制提供关键的见解。