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.
The tethering of newly made chromosomes together, called sister chromatid cohesion is essential for many aspects of normal human health and development. Mutations in genes required for this cohesion cause severe developmental disorders such as Roberts and Cornelia de Lange syndromes. Defective cohesion is also thought to contribute to malignancy in many tumors. Finally, failures in cohesion may underlie the increase in abnormal chromosome number in human eggs that is associated with advanced maternal age. This increase leads to birth defects such as Down syndrome and Turner syndrome and is a leading cause of spontaneous abortions. The experiments in this proposal will elucidate mechanisms by which chromosomes are held together to ensure normal growth and development.
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