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Equipe de Réparation ADN
Mechanism and regulation of DNA repair

Group leader: Fabrice Fleury (PU).

Present members: Dmitri Levitsky (PU), Pierre Weigel (MCU/HDR), Houda Benhelli-Mokrani (MCU), Yvonnick Chéraud (MCU), Emmanuelle Courtois (TU), Gwennina Cueff (TU), Damien Marquis (TU), Carine Pruvost (AJTU), Thomas Chabot (PhD student), Alexandre Demeyer (PhD student).

Contracts in progress: Région TransMed (2015-2017), Piramid (2016-2020) et Ligue contre le Cancer (2015-2016).

Projects and goals: Our main objective is to understand the molecular and biochemical mechanisms of DNA repair, including homologous recombination (HR), and to explore DNA repair pathways involved in the process of resistance to anticancer therapy..
We are interested in Rad51, a key protein to HR. This protein is frequently overexpressed in cancer cells and can lead to radio- and chemoresistance.
Interactions involving proteins of DNA repair are studied by high-throughput screening (protein chips). Characterization and structure-function analysis are also addressed by a set of biophysical tools. All these technologies, available through the IMPACT platform, are fully controlled by our team. Thus, the molecular information extracted could be used to better understand the regulation at the cellular level. This molecular-cellular interface is one of the strengths that characterize our team..

1. DNA repair by HR

  • Rad51 is a potential target that could be used in the fight against cancer. In this context, our team seeks to understand the molecular mechanism at the different stages of the recombinase activity and to develop Rad51 inhibitors. Recently, we proposed different types of inhibitors (peptide, nucleic aptamer and chemical molecule) some of which have been proved effective in vitro.
    The improvement and the optimization of these inhibitors by molecular modeling recombinase (Team 3), lead us to evaluate these molecules at the cellular level and to confirm their efficacy against resistant cancer cells.

2. Regulation of repair pathways in response to DNA damage

In addition to studying recombinase activity modulations in vitro and in cellulo, a global analysis of the repair regulation of DNA damages is considered. Regulating Rad51 expression in/during the cell cycle is considered using Physarum polycephalum as a model system (Team 1). In parallel post-translational modifications, that are essential in the regulation of proteins involved in pathways of DNA repair, are studied. Rad51 may be directly phosphorylated by kinases like Abl or BCR-Abl, involved in cancer chemoresistance. However, relations with signaling pathways are not yet clearly established. We develop and create tools, i.e. specific antibody chip, to analyze the profiles of phosphoproteomic resistant cancer cells in order to identify activation pathways important for DNA repair. The effects and consequences of inhibitors on Rad51 activity are also analyzed and evaluated in the ways of DNA repair.