Mechanisms preventing DNA replication between Meiosis I and Meiosis II
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.
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| Other Authors: | |
| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2018
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| Online Access: | http://hdl.handle.net/1721.1/117786 |
| _version_ | 1811097444109254656 |
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| author | Phizicky, David V. (David Vincent) |
| author2 | Stephen P. Bell. |
| author_facet | Stephen P. Bell. Phizicky, David V. (David Vincent) |
| author_sort | Phizicky, David V. (David Vincent) |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018. |
| first_indexed | 2024-09-23T16:59:38Z |
| format | Thesis |
| id | mit-1721.1/117786 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:59:38Z |
| publishDate | 2018 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1177862019-04-11T05:13:14Z Mechanisms preventing DNA replication between Meiosis I and Meiosis II Phizicky, David V. (David Vincent) Stephen P. Bell. 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, 2018. This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. Cataloged student-submitted from PDF version of thesis. Includes bibliographical references. The vast majority of multicellular organisms reproduce using sexual reproduction, which requires the production of haploid gametes. These gametes are produced by meiosis, a specialized cell division during which one round of DNA replication is followed by two rounds of chromosome segregation, Meiosis I (MI) and Meiosis II (MII). This imbalance between rounds of DNA replication and chromosome segregation causes diploid cells to produce haploid gametes. In contrast, mitotically-dividing cells maintain ploidy by alternating between rounds of replication and segregation. It is unclear how meiosis accomplishes two sequential chromosome segregation events without an intervening round of DNA replication. In mitotic cells, both DNA replication and chromosome segregation are regulated by oscillations of cyclin-dependent kinase (CDK) activity. Both events initiate during G1 due to the associated low CDK-activity state, and both events are completed later in the cell cycle due to increased CDK activity. During meiosis, uncoupling replication and segregation presents a unique problem. After completion of MI, CDK activity decreases and then increases to drive MII chromosome segregation. However, DNA replication must remain inhibited between MI and MII. Given that an oscillation of CDK activity is sufficient for genome re-duplication in mitotic cells, I sought to understand how meiotic cells prevent DNA replication while resetting the chromosome segregation program. In this thesis, I show that meiotic cells inhibit two distinct steps of DNA replication: (1) loading of the replicative helicase onto replication origins, and (2) activation of the replicative helicase. CDK and the meiosis-specific kinase Ime2 cooperatively inhibit helicase loading during the meiotic divisions, and their simultaneous inhibition causes inappropriate helicase reloading. Further studies of Ime2 revealed two mechanisms by which it inhibits this process. First, I showed that Ime2-phosphorylation of the helicase directly inhibits its loading onto origins. Second, Ime2 cooperated with CDK to transcriptionally and proteolytically repress Cdc6, an essential helicase-loading protein. In addition, I found that meiotic cells use CDK and the polo-like kinase Cdc5 to promote degradation of Sld2, an essential helicase-activation protein. Together, these data demonstrate that multiple kinases inhibit both helicase loading and activation between MI and MII, thereby ensuring a reduction in ploidy. by David V. Phizicky. Ph. D. 2018-09-17T14:49:34Z 2018-09-17T14:49:34Z 2018 2018 Thesis http://hdl.handle.net/1721.1/117786 1051190596 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 117 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Phizicky, David V. (David Vincent) Mechanisms preventing DNA replication between Meiosis I and Meiosis II |
| title | Mechanisms preventing DNA replication between Meiosis I and Meiosis II |
| title_full | Mechanisms preventing DNA replication between Meiosis I and Meiosis II |
| title_fullStr | Mechanisms preventing DNA replication between Meiosis I and Meiosis II |
| title_full_unstemmed | Mechanisms preventing DNA replication between Meiosis I and Meiosis II |
| title_short | Mechanisms preventing DNA replication between Meiosis I and Meiosis II |
| title_sort | mechanisms preventing dna replication between meiosis i and meiosis ii |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/117786 |
| work_keys_str_mv | AT phizickydavidvdavidvincent mechanismspreventingdnareplicationbetweenmeiosisiandmeiosisii |