Regulation of meiotic recombination : DNA double-strand break formation and repair in C. elegans
Abstract/Contents
- Abstract
- Sexually reproducing organisms undergo meiotic recombination to increase genetic diversity and to ensure correct segregation of chromosomes at the first meiotic division. During meiotic recombination, DNA double-strand breaks (DSBs) are deliberately induced, and a subset of the breaks are repaired as inter-homolog crossovers (COs). Inter-homolog COs provide physical connections between homologous chromosomes that enable them to segregate away from each other. Despite reliance on COs for chromosome segregation, few COs are made per chromosome pair, implying mechanisms for robust CO control. In addition, DNA breaks are potentially dangerous lesions, therefore DSB formation and repair must be tightly regulated, both to ensure the formation of COs, but also to protect against deleterious effects. This thesis provides new insights into mechanisms that regulate DSB formation and repair, using the nematode Caenorhabditis elegans as a model organism. CO regulation mechanisms were probed by monitoring the repair outcome of a DSB induced at a defined site at different stages of meiotic progression, in WT and mutant situations. This analysis uncovered a previously unappreciated level of control in restricting CO number, which is to limit the duration of access to the homolog as a repair template. In addition, this work showed that when no competing breaks are present, a single induced DSB is converted to a CO with high efficiency. This feature helps achieve CO assurance. Insights into regulation of DSB formation were uncovered from the identification and characterization of novel protein DSB-2. DSB-2 is required for break formation, but is dispensable for later steps of meiotic recombination. DSB-2 localizes to chromatin during the time of break formation, suggesting it acts to promote competence for DSB formation. Both approaches presented in this thesis uncovered evidence for negative feedback regulatory mechanisms, suggesting a model wherein formation of CO-eligible recombination intermediates signals shutdown of DSB formation as well as shutdown of inter-homolog access. The proposed regulatory networks provide a mechanism to both ensure sufficient breaks and COs are made, and to shut down these processes to prevent deleterious effects as meiosis progresses.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Rosu, Simona |
|---|---|
| Associated with | Stanford University, Department of Genetics |
| Primary advisor | Villeneuve, Anne, 1959- |
| Thesis advisor | Villeneuve, Anne, 1959- |
| Thesis advisor | Cimprich, Karlene |
| Thesis advisor | Fire, Andrew Zachary |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Advisor | Cimprich, Karlene |
| Advisor | Fire, Andrew Zachary |
| Advisor | Lipsick, Joseph Steven, 1955- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Simona Rosu. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2012. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Simona Rosu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial No Derivatives 3.0 Unported license (CC BY-NC-ND).
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