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. BRCA2 interacts with RAD51 through eight short repeats with different affinities, and through an additional C-terminal BRCA2 domain. Nowadays, only the interaction of RAD51 with the fourth BRC repeat, has been structurally characterized while it is not completely clear the role of other BRC sequences. Nevertheless, the interaction of RAD51 with multiple BRC repeats may imply a tight and fine regulation of RAD51 activity.
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 through an extensive structural, kinetic and thermodynamic characterization of RAD51 interaction with the single BRC repeats and with multiple BRC repeats constructs of different lengths.
