Regulation of chromosome cohesion during cell cycle progression

在DNA复制之后，每个染色体的两个相同的拷贝被保持在一起，直到 细胞分裂的过程称为姐妹染色单体凝聚。姐妹染色单体凝聚力是 对于准确的染色体分离，修复DNA损伤，维持 转录程序和正常发育。凝聚力基因突变导致出生缺陷 并与某些癌症相关的基因组不稳定有关。凝聚力方面的失败有 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的主要原因 缺陷和自然流产。 姐妹染色单体的凝聚力是由一种称为粘附素的大型蛋白质复合体介导的。的活动 必须调节这种复合体，以确保粘附素被放置在染色质上并在 这是一种与DNA复制和细胞周期进程相结合的方式。这项规定是 通过几种蛋白质的活动来完成，这些蛋白质共同调节细胞的稳定性 粘附素-染色质相互作用。在这里，我们提出了一系列实验来定义这些 蛋白质，我们称之为“粘附素稳定网络”，在DNA复制和在 对细胞周期进程的反应。结合使用生化和细胞生物学的方法， 包括在培养细胞和青蛙卵提取物中的分析，我们将定义功能相互作用 在粘附素复合体和这个调控网络之间。这些实验的结果将 对建立、维护和维护凝聚力的机制提供批判性见解 在脊椎动物系统中重塑。

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.