Regulation of chromosome cohesion during cell cycle progression

细胞周期进程中染色体凝聚力的调节

基本信息

批准号：
9918789
负责人：
Susannah Rankin
金额：
$ 12.12万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918789
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 DNA replication fork Daughter Development Down Syndrome Ensure Enzymes Event Excision Failure Genes Genetic Transcription 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 Regulation 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 chromosome number abnormality cohesin cohesion developmental disease differential expression egg experimental study improved insight programs protein complex protein function recruit response telophase tumor

项目摘要

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.

DNA复制后，每个染色体的两个相同的副本都被固定在一起直到通过称为姐妹染色单体内聚的过程细胞分裂。姐妹染色单体的凝聚力是对于准确的染色体分离，维修DNA损伤，维持的维护至关重要转录程序和正常发展。内聚力基因的突变导致出生缺陷并与与某些取消相关的基因组不稳定性有关。凝聚力失败是被认为是母亲与年龄相关的非整倍卵的增加的基础，这是主要的出生原因缺陷和赞助流产。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。活动必须调节该复合物，以确保在染色质上放置粘蛋白并在A中激活与DNA复制和细胞周期进程集成的方式。这个法规是通过几种蛋白质的活性来实现，以调节调节的稳定性粘蛋白 - 染色质相互作用。在这里，我们提出了一系列实验，以定义这些实验在DNA复制期间，我们将蛋白质配音为“粘蛋白稳定网络”，并在对细胞周期进程的反应。结合生化和细胞生物学方法，包括在培养的细胞和青蛙卵提取物中的测定，我们将定义功能相互作用在粘蛋白复合物和该调节网络之间。这些实验的结果将对建立，维护的凝聚力的机制提供批判性洞察力，并在脊椎动物系统中进行了改建。