The spindle checkpoint is conserved from yeast to human. When the chromosomes are not properly attached to the spindle, the spindle checkpoint delays anaphase onset through inhibiting the E3-ubiquitin ligase APC/C (Anaphase Promoting Complex/Cyclosome) and its co-activator Cdc20. The spindle checkpoint proteins are first identified in budding yeast, which include Bub1 (Budding Uninhibited by Benomyl), Bub3, Mad1 (Mitotic Arrest Deficient), Mad2, and Mad3. My thesis work focuses on characterizing novel functions of the spindle checkpoint protein Bub3 in mitosis and meiosis. In mitosis, I found that when the spindle checkpoint is not activated, deleting BUB3 results in a delayed anaphase onset, and impaired binding of APC/C and its co-activator Cdc20. Furthermore, Bub3 kinetochore localization is required for the normal binding between APC/C and Cdc20. These results suggest that, surprisingly, Bub3 promotes the metaphase-to-anaphase transition in a normal cell cycle by activating APC/C. We propose a model that Bub3 enhances the binding between APC/C and Cdc20 in a normal cell cycle, and activates the APC/C at the kinetochore; but when the spindle checkpoint is activated, Bub3 cooperates with other checkpoint proteins to inhibit APC/C activity. This counter-intuitive yet intriguing role of Bub3 adds a new layer of APC/C activity regulation in mitosis. Bub3’s role in meiosis is unclear. Studying the spindle checkpoint in meiosis is of great medical relevance, because defects in the spindle checkpoint cause chromosome mis-segregation, which could result in birth defects. My preliminary results show that depletion of Bub3 in meiosis causes a defect in entering the meiotic divisions and sporulation. This result suggests that Bub3 has a novel role in promoting early meiotic progression. Collectively, my findings in the thesis work uncovered previously unknown functions of the spindle checkpoint protein Bub3 in cell cycle regulation, and contribute to a more comprehensive understanding of the spindle checkpoint function in mitosis and meiosis.
|Commitee:||Calvi, Brian, Hu, Ke, Pikaard, Craig|
|School Location:||United States -- Indiana|
|Source:||DAI-B 77/10(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology, Cellular biology|
|Keywords:||Amaphase promoting complex, Anaphase, Mitosis, Spindle checkpoint|
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