A stress response that allows highly mutated eukaryotic cells to survive and proliferate
| Autor: | Daniel F. Jarosz, Richard She, Rebecca Ann Zabinsky, Michelle K. Zeman, Jonathan Mares, Thomas R. Silvers |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Genetics
0303 health sciences Mutation rate Genetic variants Biology Yeast Fight-or-flight response 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis Gene expression Mutation (genetic algorithm) Genetic variation Transcriptional response 030304 developmental biology |
| DOI: | 10.1101/515460 |
| Popis: | Rapid mutation fuels the evolution of many cancers and pathogens. Much of the ensuing genetic variation is detrimental, but cells can survive by limiting the cost of accumulating mutation burden. We investigated this behavior by propagating hypermutating yeast lineages to create independent populations harboring thousands of distinct genetic variants. Mutation rate and spectrum remained unchanged throughout the experiment, yet lesions that arose early were more deleterious than those that arose later. Although the lineages shared no mutations in common, each mounted a similar transcriptional response to mutation burden. The proteins involved in this response formed a highly connected network that has not previously been identified. Inhibiting this response increased the cost of accumulated mutations, selectively killing highly mutated cells. A similar gene expression program exists in hypermutating human cancers and is linked to survival. Our data thus define a conserved stress response that buffers the cost of accumulating genetic lesions and further suggest that this network could be targeted therapeutically. |
| Databáze: | OpenAIRE |
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