Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2021
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| Online Access: | https://hdl.handle.net/1721.1/130663 |
| _version_ | 1826217894996869120 |
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| author | Maier, Nolan Kenji Kwaisun. |
| author2 | Iain Cheeseman. |
| author_facet | Iain Cheeseman. Maier, Nolan Kenji Kwaisun. |
| author_sort | Maier, Nolan Kenji Kwaisun. |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021 |
| first_indexed | 2024-09-23T17:10:45Z |
| format | Thesis |
| id | mit-1721.1/130663 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T17:10:45Z |
| publishDate | 2021 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1306632021-05-25T03:00:46Z Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition Maier, Nolan Kenji Kwaisun. Iain Cheeseman. Massachusetts Institute of Technology. Department of Biology. Massachusetts Institute of Technology. Department of Biology Biology. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021 Cataloged from the official PDF of thesis. "February 2021." Includes bibliographical references. To generate haploid gametes, meiotic cells must undergo two consecutive rounds of chromosome segregation without an intervening gap phase. Importantly, because homologous chromosomes are segregated in meiosis I, but sister chromatids are segregated in meiosis II, this requires a dramatic rewiring of the cell division machinery between the two divisions. How meiotic cells coordinate this rapid and substantial change to the cell division machinery is a central mystery at the heart of proper fertility and reproduction. Our work reveals a new paradigm that rewires key cell division processes at the meiosis I/II transition through the action of the protease Separase, which we demonstrate acts by cleaving the meiosis-specific kinetochore protein Meikin. Cleavage of Separase substrates such as cohesin results in their potent and complete inactivation. In contrast, we find that Separase cleavage of Meikin acts as a molecular "scalpel," providing an elegant mechanism to precisely and irreversibly modulate Meikin activity between the two meiotic divisions without inactivating Meikin function. Our results demonstrate that the C-terminal Meikin cleavage product generated by Separase proteolysis retains substantial activity such that it localizes to kinetochores, binds to Plk1 kinase, and promotes downstream activities such as the cleavage of the meiosis-specific cohesin subunit Rec8, similar to full length Meikin. Importantly, we demonstrate that both the failure to cleave Meikin or the complete inactivation of Meikin at the meiosis I/II transition each result in dramatic defects in the proper execution of meiosis II. Our functional analysis in mouse oocytes demonstrates that precise Meikin cleavage is critical to differentially control meiosis I and II. Thus, in contrast to previous models, Meikin is not just a regulator of meiosis I-specific activities, but differentially coordinates chromosome segregation across both meiotic divisions. Our discovery of Meikin as a new substrate for Separase cleavage represents a novel mechanism for the regulatory control of the meiosis I/II transition. by Nolan Kenji Kwaisun Maier. Ph. D. Ph.D. Massachusetts Institute of Technology, Department of Biology 2021-05-24T19:39:39Z 2021-05-24T19:39:39Z 2020 2021 Thesis https://hdl.handle.net/1721.1/130663 1251767286 eng MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided. http://dspace.mit.edu/handle/1721.1/7582 92 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Maier, Nolan Kenji Kwaisun. Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition |
| title | Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition |
| title_full | Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition |
| title_fullStr | Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition |
| title_full_unstemmed | Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition |
| title_short | Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition |
| title_sort | separase cleaves the kinetochore protein meikin to direct the meiosis i ii transition |
| topic | Biology. |
| url | https://hdl.handle.net/1721.1/130663 |
| work_keys_str_mv | AT maiernolankenjikwaisun separasecleavesthekinetochoreproteinmeikintodirectthemeiosisiiitransition |