Author ORCID Identifier

https://orcid.org/0009-0008-7828-4724

Date of Award

Spring 5-15-2025

Document Type

Thesis (Ph.D.)

Department or Program

Biological Sciences

First Advisor

Sharon Bickel

Second Advisor

Erik Griffin

Third Advisor

Arminja Kettenbach

Abstract

Meiotic chromosome segregation errors in human oocytes are the leading cause of miscarriages and aneuploid pregnancies, and these errors increase dramatically as women age. Using Drosophila oocytes as a model system, this dissertation identifies the NAD⁺-dependent deacetylase Sirt1 as a key regulator of chromosome segregation and meiotic arm cohesion. Loss of Sirt1 activity during meiotic prophase leads to premature loss of arm cohesion and increased segregation errors in Drosophila oocytes. In addition, elevated acetylation of its substrate, histone H4K16, indicates that Sirt1 activity declines in oocytes during aging. Strikingly, dietary administration of the Sirt1 activator SRT1720 preserves Sirt1 deacetylase activity on oocyte chromosomes during aging and significantly suppresses age-dependent segregation errors.

In addition to describing an essential role for Sirt1 in the accurate segregation of meiotic chromosome segregation, this dissertation also identifies proteins that suffer oxidative damage during oocyte aging. A biochemical approach identified BubR1 as one of several proteins that sustain significant aging-induced oxidation. Moreover, functional analysis of flies harboring a mutation in the kinase domain of BubR1 supports the model that BubR1 kinase activity is required to promote meiotic cohesion. Together, these findings deepen our understanding of the molecular drivers of age-related meiotic errors and may inform novel intervention strategies to improve reproductive outcomes in aging oocytes.

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