The interaction of RAD51 and BRCA2, two proteins involved in the homologous recombination (HR) pathway for the repair of DNA double strand breaks (DSB) is a key-process for the integrity of our genome. BRCA2 recruits, transports and assist RAD51 to the sites where DNA damages are processed. Alterations of their interactions, which have been associated to cancer development, lead to defects in the DNA DSB repair pathway. This project aims at elucidating the mechanism, most likely designed, to fine tune the RAD51-BRCA2 interaction. The goal is to unveil mechanistic details to clarify the tight correlation between these two proteins, their interaction and cancer propensity. We will perform an extensive structural, kinetic and thermodynamic characterization of RAD51 interaction with the single BRC repeats and with multiple BRC repeats constructs of different lengths. Then, we will perform a combination of biological assays in non-tumoral and tumoral cell lines with different modified BRC peptides to test their ability of impairing the RAD51-BRCA2 interaction and therefore the HR pathway thus enhancing the toxicity of anticancer drugs. The multidisciplinary presented project will allow a thorough description of the RAD51-BRCA2 mechanism of interaction pivotal for the control of genome integrity.
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Unveiling the molecular mechanism of BRCA2-RAD51 interaction to tackle cancer onset