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Laboratory | Stress response | Toxicology | Nuclear Toxicology
ManagerStéphane CHEDIN+33 1 69 08 97 firstname.lastname@example.org
The cellular response to stress conditions involves specific transcriptional programmes that are characterized by the rapid and massive induction of dedicated genes. We are interested in understanding how these programmes are implemented, regulated and prioritized.
Over the past years, we focused on the mechanisms used by the eukaryotic model S. cerevisiae to respond to toxic metals such as cadmium. The thiol-containing antioxidant glutathione is a key player of cadmium detoxification. We demonstrated that cadmium triggers a programme of substitution of abundant glycolytic enzymes by isoforms with lower sulfur content. This programme is orchestrated by the activator Met4 and results in more cysteine available for glutathione synthesis. It also makes the enzymatic machinery for metabolizing glucose probably less vulnerable to the damaging effects of cadmium.
We are currently studying how transcriptional programmes induced during stress-response interfere with each other in case of multiple stresses, and how these programmes impact the overall transcriptional activity of the cell. Our works focus on gene-specific transcription factors, but also on the Mediator coactivator complex, chromatin regulators and general transcription factors.
The cellular response to H2O2 requires the activation, through signaling pathways, of transcriptional effectors that are essential to preserve cell viability. We demonstrated that in S. cerevisiae, the two cytoplasmic thioredoxins, Trx1 and Trx2, are required to trigger the activation and the nuclear accumulation of transcriptional effectors. More recently, we showed that a very low amount of glutathione is necessary and sufficient to preserve cell viability upon oxidative stress. We propose that the essential role of glutathione upon H2O2 treatment is to shield nuclear functions against oxidative injury.
We are now investigating the molecular mechanisms underlying the protective role of glutathione during oxidative stress, both at the level of the transcriptional response and at the level of DNA checkpoint activation.
Thanks to our basic research, we acquired a strong expertise in the study of molecular mechanisms of metal toxicity. This led us to tackle projects to address societal issues such as the toxicity of nanoparticles. To this purpose, we developed a new strategy for sorting proteins that bind to the surface of nanoparticles from proteins resistant to adsorption. Based on statistical comparisons of these two subsets, we highlighted physicochemical rules of protein adsorption and non-adsorption, which will be used to predict nanoparticles toxicity. Finally, we are interested in characterizing the molecular response to tritium (3H) exposure. For this, we use tritium-carrying molecules to address tritium to different cellular macromolecules and compare the stress-responses by transcriptomic and proteomic approaches.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.