When cells divide, cohesion between sister chromatids provides a physical mechanism to hold sister chromatids together from the time of their synthesis until they segregate to opposite poles. During both mitosis and meiosis, cohesion is essential for accurate chromosome segregation. For at least 5% of all clinically recognized human pregnancies, errors in meiotic segregation give rise to aneuploid zygotes. Moreover, defects in meiotic chromosome segregation are dramatically more prevalent in older women. Our long-term goal is to understand how chromosome segregation is regulated at the molecular level and why errors in segregation occur more frequently in older oocytes. We will use genetic, cytological and biochemical strategies to study the mechanisms that control meiotic sister-chromatid cohesion and chromosome segregation in the model organism Drosophila. ORD protein is essential for meiotic cohesion in Drosophila males and females. We have shown that ORD associates with meiotic chromosomes in both sexes, and controls the association of cohesin subunits with meiotic chromosomes. To elucidate the mechanism by which ORD controls cohesin localization, we will test the hypothesis that ORD is a meiotic cohesin subunit and define the requirements for arm and centromeric localization of ORD and cohesin SMCs. We will continue our characterization of gene products that interact with ORD and use genetic techniques to indentify additional ORD interactors. Analysis of these proteins will be critical in elucidating the mechanism by which ORD promotes cohesion and also will further our understanding of the overall pathway of events required for proper chromosome segregation during Drosphila meiosis. Finally, we have developed an experimental system that will allow us to test the hypothesis that deterioration of cohesion during aging causes defects in chromosome segregation in older eggs. In addition, we will will use genetic and proteomic approaches to identify gene products that influence age-dependent nondisjunction.
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