NSF Award
0132237
The goal of this work is to define the regulatory mechanisms that ensure accurate segregation of the sister chromatids in mitosis and meiosis. Drosophila is a powerful model organism in which to decipher the control of chromosome segregation for three reasons: 1) chromosome dynamics can be visualized directly; 2) genetic tools allow ready detection of mutants defective in segregation; and 3) it is possible to ablate gene function using RNAi in order to evaluate the role of genes identified in other species. This research focuses on proteins that control two crucial aspects of chromosome dynamics: sister-chromatid cohesion and condensation. In order for sister chromatids to move away from each other during anaphase they must first be physically attached to each other. This ensures that each sister chromatid of a pair attaches to microtubules emanating from opposite spindle poles. Cohesion must be precisely regulated to release only as the sisters separate at anaphase. The Drosophila MEI-S332 protein binds to centromeres to maintain cohesion and is essential during meiosis. The cohesin complex of proteins is essential both for the establishment of cohesion during DNA replication and its maintenance until chromatid separation at anaphase. The cohesin complex acts along the length of the chromosomes in mitosis and meiosis I and maintains cohesion at the centromere in meiosis II. This research addresses the mechanism by which MEI-S332 localization to centromeres is regulated and analyzes the relationship between MEI-S332 and the cohesin protein complex. The condensin complex is necessary for chromosome condensation, and mutations have been recovered in the gene encoding one of the subunits. This project will define the interdependency of the cohesin and condensin complexes. The role of the condensin complex in meiosis and gene expression also will be investigated. Three collections of mutants with defects in segregation have been recovered and will be analyzed to determine the activities of the gene products. The phenotypes indicate that these genes play critical roles in chromosome segregation, thus their investigation will provide new insights into chromosome dynamics.<br/><br/>This research investigates the control of chromosome segregation, with the goal of deciphering two fundamental aspects essential for the proper partitioning of chromosomes during cell division. Accurate segregation of chromosomes is essential during the divisions that produce sperm and eggs in order to avoid birth defects such as Down Syndrome. Inaccurate segregation during cell proliferation produces aneuploid cells; these cells with an incorrect number of chromosomes are prone to become transformed cancer cells. The mechanisms that ensure proper segregation remain to be elucidated. This basic research builds on the identification of proteins known to participate in chromosome segregation to unravel the dynamics of chromosome behavior.
