Non-random chromosome segregation in mouse embryonic stem cells

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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.