GENMAINEVO · Genome maintenance and evolution
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-05-01 → 2023-04-30
- EU contribution
- €147,815
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Genome maintenance and evolution
Mutations that disrupt crucial cellular processes, such as DNA replication, frequently result in significant impairments in growth. When these defects are not lethal, they exert substantial selective pressure on cells, often leading to pathological conditions such as cancer and premature aging. Recent investigations have elucidated the rapid evolutionary adaptations of cells to mutations, even when they disrupt essential and conserved processes. Constitutive exposure of cells to replication stress instigates the accumulation of DNA damage and, ultimately, genetic instability. Presently, the impact of environmental cues on the evolutionary adaptation to intracellular selective pressure remains unknown. Among these cues, nutrient availability is a prominent variable influencing several processes, including regulating the cell cycle and ensuring that these processes occur only under favorable conditions. In this project, we investigated the influence of nutrient availability and nutrient sensing on the evolutionary adaptation to DNA replication stress. Our findings demonstrate that although various nutrient conditions affect cell growth and the cell cycle, the evolutionary strategies enabling cells to adapt to DNA replication stress are conserved. These results underscore the robustness of this evolutionary process in the face of environmental fluctuations. The implications of our research are pertinent to the identification of potential therapeutic targets for the treatment of tumors or genetic diseases associated with premature aging.
Data: CORDIS, © European Union
Project objective
Genome maintenance describes a subset of conserved cellular processes responsible for the faithful propagation of genomes across cell divisions. Defects in genome maintenance have been associated with several medical disorders such as cancer, aging and developmental defects. Recently we showed how perturbations in DNA replication, one of the most conserved processes in genome maintenance, induce an evolutionary process that leads to the sequential and concerted accumulation of adaptive mutations that increase the cellular fitness in response to replication stress. To what extent this fast-evolutionary rescue applies to other defects in genome maintenance, and what evolutionary trajectories are responsible for adaptation under different cellular stresses remain unexplored questions. Furthermore, while adaptive mutations rewire genetic networks to achieve increased fitness, their pleiotropic effect on cell biology is unknown. Here I propose a plan to comprehensively investigate these questions by taking advantage of a multi-disciplinary methodology using the budding yeast S. cerevisiae as a eukaryotic model organism. Experimental evolution of cells perturbed in several aspects of genome maintenance will be combined with computational and quantitative approaches to study their evolutionary adaptation in response to the different initial perturbations. Molecular genetics and cell biology techniques will be then used to investigate the consequence of these adaptations to cell’s sensitivity to genotoxic agents, a phenotype directly relevant for the treatment of medical-relevant diseases including cancer and infection diseases. The knowledge generated by the proposed research project will reveal important aspects of how cells adapt to genetic perturbations, with implications for both medical therapies and evolutionary cell biology at large.
Original text from CORDIS.
Participants
- FUNDACAO CALOUSTE GULBENKIAN · LisboaCoordinatorPortugal
Links
Data: CORDIS, © European Union