Project Summary Homologous chromosomes enter meiosis unconnected to each other, but they become linked by crossovers (exchanges). These linkages help the homologous chromosomes to move away from each other in meiosis I. The linkages transmit tension between the homologous centromeres when they become attached to microtubules from opposite sides of the spindle (bi-oriented). Tension stabilizes these microtubule attachments. Accordingly, failures in crossing-over can result in meiotic errors and aneuploid gametes. The pairing of homologous centromeres (CEN-pairing) in meiotic prophase, is a recently discovered, conserved phenomenon. In yeast, CEN-pairing helps the partner chromosomes, later, in anaphase I, to segregate properly, even if they have failed to experience a crossover. The mechanism by which CEN-pairing promotes segregation is unknown. While crossover formation has been investigated for decades, very little is known about how CEN-pairing promotes meiotic chromosome segregation. This is the focus of our proposal. In Aim 1 we test the hypothesis that the CEN-pairing allows the formation of centromere-centromere connections that improve the segregation fidelity of meiotic chromosome partners. We will use live cell imaging to monitor the meiotic behavior of chromosome pairs have or have not undergone CEN-pairing. In Aim 2 we will test the hypothesis that connections formed during CEN-pairing are mediated by cohesin proteins. Aim 3 will explore mechanism by which centromere-centromere connections help partner chromosomes become bi-oriented on the spindle. We will directly measure the spring-like properties of the centromere-to-centromere connections using bio-physical approaches and test whether partners with a centromere-centromere connection can use the tension-sensing signaling pathways. In addition, these experiments will test the hypothesis that centromere-centromere connections are important to improve the segregation fidelity of chromosome pairs linked by crossovers that alone would be ineffective in creating a tension-transmitting bridge as the pair attaches to microtubules. Together, the experiments in this project will elucidate the reasons that some crossovers do, and some don?t, effectively ensure high fidelity chromosome segregation in meiosis and will explain how the recently described process of centromere pairing can mediate the formation of a centromere- to-centromere connection between homologs that augments the functionality of crossovers, or can act alone when crossovers fail.

R01GM138889

2021-04-01

2024-12-31