Non-random chromosome segregation in mouse embryonic stem cells

描述（由申请人提供）：本研究的长期目标是了解小鼠胚胎干细胞中非随机染色单体分离的分子机制。永生链假说——假设干细胞将所有染色体中“最古老”的DNA链不对称地分离给自我更新的干细胞，作为一种机制，以防止干细胞继承任何可能导致癌症状态的DNA复制错误。干细胞利用这一策略在染色体的基础上指导特定染色单体的分离。具体而言，小鼠胚胎干细胞选择性分离7号染色体染色单体，我们提出确定其机制。这项提议有两个目的。第一个目的是测试假设，非随机染色单体分离取决于DNA的复制年龄使用染色体定向荧光原位杂交（CO-FISH）。第二个目标将测试LRD，外臂2轴系动力蛋白重链的同源物，作为一个分子马达来指导非随机染色单体分离的假设。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular mechanism of non-random chromatid segregation in mouse embryonic stem cells. The immortal strand hypothesis - posits that stem cells segregate the "oldest" DNA strands of all chromosomes asymmetrically to the self-renewing stem cells as a mechanism to prevent the stem cell from inheriting any errors in DNA replication that could lead to a cancerous state. Stem cells use this strategy on a chromosome by chromosome basis to direct the segregation of specific chromatids. Specifically, mouse embryonic stem cells selectively segregate chromatids of chromosome 7 and we propose to determine the mechanism. This proposal has two Aims. The first Aim is to test the hypothesis that non-random chromatid segregation depends on the replicative age of the DNA using chromosome oriented fluorescence in situ hybridization (CO-FISH). The second aim will test the hypothesis that LRD, a homolog of outer-arm 2-axonemal dynein heavy chain, functions as a molecular motor to direct non-random chromatid segregation. PUBLIC HEALTH REVELANCE: Stem cells are unique in having the ability to "self renew" and at the same time to be capable of differentiating into every cell in the body. It is critical that stem cells have mechanisms that protect their genetic integrity so that they may maintain their stem cell identity while faithfully executing the instructions needed to adopt many different cellular fates. One mechanism that stem cells use is to selectively segregate chromosomes after they are replicated so that specific copies are kept together. This is a mysterious process since we generally believe that replicated chromosomes are segregated randomly. Clearly, stem cells are different in this regard. The goal of this research is to understand the mechanism of selective chromosome segregation in stem cells.