Date of Award
Spring 2024
Document Type
Thesis (Ph.D.)
Department or Program
Biological Sciences
First Advisor
Sharon Bickel
Second Advisor
Giovanni Bosco
Third Advisor
James Moseley
Abstract
During meiosis, faithful segregation of chromosomes requires maintenance of sister chromatid cohesion from premeiotic S phase until its stepwise dissolution at anaphase I and anaphase II. Research in humans and model organisms indicates that premature loss of meiotic cohesion is a major determinant of age-induced aneuploidy in human oocytes, a phenomenon known as the maternal age effect. Because cohesin turnover after S phase has not been detected in mice oocytes, the prevailing model for mammalian oocytes is that cohesion cannot be replenished after its initial establishment in S phase. However, previous research from the Bickel lab suggested that a cohesion rejuvenation program operates in Drosophila oocytes to maintain sister chromatid cohesion during meiotic prophase by generating new cohesive linkages. This dissertation presents the first evidence that cohesin expressed during meiotic prophase is used to form new cohesive linkages as part of a cohesion rejuvenation program. In addition, my work demonstrates that, as a result of extensive cohesin turnover, cohesin along the chromosome arms can be completely replaced multiple times during meiotic prophase in Drosophila oocytes. Furthermore, cohesin loading on chromosome arms is facilitated by the cohesin loader Nipped-B, and lack of cohesin loading during meiotic prophase results in premature cohesion loss. To identify factors specifically involved in cohesion rejuvenation during meiotic prophase and not S phase establishment, I performed a genetic screen and identified 29 proteins that are required during meiotic prophase for accurate chromosome segregation in Drosophila oocytes. Further investigation of two positive hits revealed that Brahma and Pumilio are essential for maintenance of arm cohesion during meiotic prophase, potentially by regulating Nipped-B-dependent cohesin loading. The work presented here describes a validated approach to identify proteins specific to the prophase rejuvenation pathway and provides new insight into the mechanisms governing rejuvenation of meiotic cohesion in oocytes. Findings in this dissertation have the potential to advance our understanding of the mechanisms underlying cohesion maintenance during the prolonged meiotic prophase in human oocytes and defects that lead to the maternal age effect.
Recommended Citation
Haseeb, Muhammad Abdul, "Formation of new cohesive linkages and regulation of cohesion rejuvenation during meiotic prophase in Drosophila oocytes" (2024). Dartmouth College Ph.D Dissertations. 261.
https://digitalcommons.dartmouth.edu/dissertations/261