A stress response that allows highly mutated cells to survive and proliferate
Abstract/Contents
- Abstract
- Cells, tissues, and organisms must deal with exogenous and endogenous sources of mutagenesis. High mutation rates are associated with disease, but they can also lead to more rapid acquisition of adaptive mutations. For example, in the cases of oncogenic transformation, infection, or environmental stress many cells are found to be hypermutators. However, mutations are on average deleterious. Understanding the mechanisms and pathways that cells employ to mitigate the toxicity of accumulating mutation burdens has broad implications for evolution, disease, and how biological systems tolerate the accumulation of mutations that come with stress and age. In this thesis, we present two studies utilizing Saccharomyces cerevisiae to create a model system to study the cellular response to accumulating mutation burden and a platform for high-throughput screening to identify compounds that selectively target cells with high mutation burden. We discovered a novel protective transcriptional response to accumulating mutation burden, that we term the Eukaryotic Mutation Burden Response (EMBR). We additionally identified the key regulator of EMBR induction: the transcriptional regulator UME6. Components of EMBR are required for cells to survive the toxicity of mutation burden. Likewise, UME6 is necessary to tolerate protein-folding stress and is required to survive accumulating mutation burden. Lastly, we identified a structurally diverse set of compounds that selectively target cells with high mutation burdens. These compounds implicate double-strand break repair and calcium homeostasis as additional mechanisms that protect against the toxicity of accumulated mutations and provide potential avenues for future development of therapeutics that target the mechanisms that cancers and pathogens use to survive mutation burden
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Mares, Jonathan |
|---|---|
| Degree supervisor | Jarosz, Daniel |
| Thesis advisor | Jarosz, Daniel |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Sherlock, Gavin |
| Thesis advisor | Wandless, Thomas |
| Degree committee member | Mochly-Rosen, Daria |
| Degree committee member | Sherlock, Gavin |
| Degree committee member | Wandless, Thomas |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jonathan Mares |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Jonathan Mares
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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