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Title: Cohesin dynamics during meiotic prophase
Author: Testori, Sarah
ISNI:       0000 0005 0734 1753
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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For faithful segregation during meiosis, chromosomes must be physically linked by both sister chromatid cohesion (SCC), provided by cohesin, and at least one crossover (CO). In mitosis, cohesin is dynamically associated with chromatin and this has been shown to be crucial for the repair of DSBs. Although DSBs are purposely made to start meiotic recombination, it is unknown if meiotic cohesin is dynamically associated with chromatin. However, cohesin loss or degradation is thought to be involved in the high incidence of aneuploidy observed in human eggs. In Caenorhabditis elegans (C. elegans), the cohesin loader SCC-2 remains associated with the axial element of meiotic chromosomes following the completion of S-phase, hinting that cohesin may be reloaded during meiotic prophase. To confirm this, I investigated if depleting SCC-2 by RNAi after entrance into meiotic prophase had an effect on cohesin association with chromosomes. This revealed loss of the cohesin subunit REC-8 from late prophase nuclei, suggesting that without reloading cohesin is removed from chromatin. Furthermore, scc-2 RNAi also resulted in the impairment of chiasmata, raising the possibility that cohesin reloading plays a role in CO formation or in chiasma maintenance. Two key mediators of cohesin removal are known to operate during the G2 phase of the mitotic cell cycle: the presence of DSBs and the cohesion anti-establishment factor Wapl1. Here I show for the first time that WAPL-1 modulates the cohesiveness of complexes containing the meiosis-specific kleisins COH-3 and COH-4. Furthermore, cohesin complexes containing different kleisins are differentially modulated by DSBs, and only REC-8-containing cohesin complexes can undertake the repair of DNA damage. Finally, I have developed several genetic tools to allow the visualization of cohesin turnover during meiosis. These findings show the exceptional complexity of cohesin dynamics during meiotic prophase, as well as demonstrating roles for cohesin outside of the provision of SCC.
Supervisor: Martinez-Perez, Enrique Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral