Periodic Reporting for period 1 - GENMAINEVO (Genome maintenance and evolution)
Okres sprawozdawczy: 2021-05-01 do 2023-04-30
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.
To elucidate the impact of nutrient availability and nutrient sensing on the adaptive response to DNA replication stress, we employed a previously established model utilizing the unicellular eukaryote Saccharomyces cerevisiae (S. cerevisiae). This model involved depriving yeast cells of Ctf4, a vital protein necessary for DNA replication, resulting in constitutive DNA replication stress. Multiple independent populations of cells were subjected to these conditions and evolved over 1000 generations. Distinct sets of populations were provided with ample nutrients, while others experienced low nutrient availability, simulating a state of cellular starvation.
Throughout the 1000 generations of evolution, cells successfully recovered from the severe DNA replication issues induced by the absence of Ctf4. To investigate the underlying genetic mechanisms of adaptation, we performed whole-genome sequencing of the final evolved populations. Remarkably, the analysis of the genomic data revealed that populations evolving under divergent nutrient conditions displayed adaptations to DNA replication stress through mutations in a common set of genes. These acquired mutations not only affected various aspects of DNA replication but also influenced two closely associated cellular processes: the cohesion of sister chromosomes and a checkpoint system responsible for detecting and responding to DNA damage.
The dissemination of the project results has occurred through different mediums. Results were published in 3 peer-reviewed papers and orally presented at 4 international conferences and 4 invited departmental seminars. Press releases on the institution's website and social media posts were published on different platforms to share these results with a wider community.
Throughout the 1000 generations of evolution, cells successfully recovered from the severe DNA replication issues induced by the absence of Ctf4. To investigate the underlying genetic mechanisms of adaptation, we performed whole-genome sequencing of the final evolved populations. Remarkably, the analysis of the genomic data revealed that populations evolving under divergent nutrient conditions displayed adaptations to DNA replication stress through mutations in a common set of genes. These acquired mutations not only affected various aspects of DNA replication but also influenced two closely associated cellular processes: the cohesion of sister chromosomes and a checkpoint system responsible for detecting and responding to DNA damage.
The dissemination of the project results has occurred through different mediums. Results were published in 3 peer-reviewed papers and orally presented at 4 international conferences and 4 invited departmental seminars. Press releases on the institution's website and social media posts were published on different platforms to share these results with a wider community.
Our study, for the first time, investigated the interaction between evolutionary pressures that act inside the cells (cellular defects) and the environmental conditions in which cells evolve. Our findings highlight the robustness of evolutionary repair processes in the face of diverse environmental conditions. Moreover, they hold significant implications for the identification of broad-spectrum therapeutic targets that could be harnessed for the treatment of a wide range of tumors, rather than being specific to certain conditions dependent on the patient's organ or age.