Description of the thesis topic

This thesis is funded by the French National Research Agency (ANR). The project is dedicated to the study of DNA repair mechanisms by homologous recombination in the context of chromatin, and the design of peptides and peptide-mimics inhibitors of protein-protein interactions for applications in cancerology.

DNA double-strand breaks induced by ionizing irradiation, genotoxic agents or blockage of DNA replication forks has to be repaired to ensure cell survival. This repair relies on repair pathways involving numerous players, including repair enzymes and factors regulating DNA accessibility, such as histone chaperones. These pathways constitute a set of potential new targets for selectively eliminating cancer cells that repair DNA breaks less efficiently.

The innovative character of this project lies in the characterization of interactions between histone chaperones and repair proteins via the homologous recombination pathway, and the design of molecules (peptides and peptidomime) interfering with these pathways for applications in oncology.

The specific objectives of this project are (i) to characterize the mode of interaction between histone chaperones and players in DNA repair pathways (ii) to design and improve by rational design peptides/ peptide-mimics that interfere with these pathways.

This project will involve the use of structural biology methods (crystallography, NMR, cryo-electron microscopy) and structure prediction (Alpha Fold, Rosetta). The candidate will also use classical protein biochemistry techniques, interaction quantification methods (ITC, BLI) and peptide synthesis in collaboration with our partner chemists.

Work Context

The I2BC is a very large CNRS, CEA and Université Paris Saclay joint research unit with a staff of almost 600. The unit comprises about 60 research teams in 5 scientific departments (Genome Biology, Cell Biology, Virology, Microbiology, Biochemistry/Biophysics/Structural Biology). Their activities are supported by 17 high-level technology platforms and shared support services.

The candidate will be integrated into the “Molecular Assembly and Genome Integrity” team within the Biochemistry, Biophysics and Structural Biology (B3S) department of the I2BC. The team is based at CEA Saclay and will move to a new Institute building on the Gif-sur-Yvette campus in 2025. The team is made up of 10 people (2 DR CEA, 1CR CEA, 1MCU, 1 tech CEA, 2 IE, 3 PhD students).

Our team combines experimental and computational strategies to elucidate the molecular basis underlying the dynamic assembly of specific protein interaction networks. Focusing on complexes involved in maintaining genome integrity, we characterize the structure of complexes, develop new methods for predicting their conformations, and design inhibitory compounds capable of disrupting these interactions.

The PhD student will be trained and supervised by thesis supervisor Francoise Ochsenbein. He/she will benefit from the team's expertise in biochemistry, structural biology and bioinformatics. He/she will have access to training courses and equipment on I2BC platforms. The project will be carried out in collaboration with teams of chemists from the University of Bordeaux and biologists from the Institut Curie and the CEA Fontenay aux Roses, within the framework of ANR collaborations.