Thursday, May 9, 2024
5/9/2024
Project Summary In both mitosis and meiosis, success depends on accurately pulling partner chromosomes away from one another on a spindle composed of microtubules. The microtubules attach to the chromosomes at their kinetochores. When the partners errantly move to the same pole a chromosome imbalance is created, producing cells with too many or too few chromosomes (aneuploidy). Meiotic errors produce aneuploid gametes, the major cause of birth defects and infertility, while aneuploidy in somatic cells is associated with tumor progression. The goal of this project is to elucidate mechanisms that allow chromosomes to correctly attach to microtubules so they segregate appropriately in meiosis and mitosis. Three concurrent projects will address this goal. Experiments in Project 1 will elucidate the mechanisms used to partition chromosomes in meiosis I. When cells enter meiosis, homologous chromosomes are not connected to each other, but they become linked by crossovers (chiasma). These linkages help homologous chromosomes to move away from each other in meiosis I. The linkages transmit tension between the homologous centromeres when they become attached correctly to microtubules from opposite sides of the spindle. Tension stabilizes these attachments. A second kind of connection called centromere pairing allows the centromeres of model chromosomes to become linked. Project 1 will explore the basis by which centromeres become connected by centromere pairing and determine how often natural chromosomes rely on centromere pairing to ensure they segregate correctly at meiosis I. Project 2 will define the biophysical properties of connections made by centromere pairing and chiasmata in transmitting tension between centromeres. Project 2 will also investigate whether chiasmata in different chromosomal positions have different biophysical properties that explain their different abilities to ensure proper segregation. A final project focuses more on mitosis. Cells with abnormally high chromosome numbers, for example many tumor cell lines and polyploid cells, rely on high level expression of the cell cycle kinase Mps1 for their survival. The same is true for meiotic cells. Mps1 plays many roles, but this Mps1-addiction of certain vulnerable cell types appears linked to a role for Mps1 in attaching chromosomes correctly to microtubules in mitosis and meiosis. The experiments in Project 3 will test the hypothesis that Mps1 mediates a form of chromosome movement called chromosome gliding that might help chromosomes move to favorable positions on prometaphase spindles. Finally, genetic screens in Mps1- addicted mammalian and yeast cells will be used to identify the vulnerable Mps1 pathways. These projects will be collaborative and synergistic and reveal unique insights into centromere behavior in meiosis and chromosome microtubule interactions in mitosis. They will include emerging technologies in budding yeast and collaborative efforts that exploit other model systems to advance our knowledge of chromosome biology.
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