What question did this study set out to answer?

This research aims to clarify the molecular interactions between BRCA2 and hRAD51 in DNA repair mechanisms, particularly focusing on their roles in cancer onset.

May 5, 2026Open Access

Unveiling the molecular mechanism of BRCA2-RAD51 interaction to tackle cancer onset

FRFrancesco RinaldiItalian Institute of Technology

Puntos clave

This research aims to clarify the molecular interactions between BRCA2 and hRAD51 in DNA repair mechanisms, particularly focusing on their roles in cancer onset.
Utilized biophysical and structural techniques to analyze the interactions between BRCA2 and hRAD51.
Investigated mutations within BRCA2's BRC repeats and their impact on BRCA2's function and RAD51 recruitment.
Identified that specific mutations in the BRC repeats disrupt BRCA2's interaction with hRAD51, correlating with cancer risk.
Provided insights into the structural aspects of the hRAD51-BRCA2 interaction, specifically elucidating the fourth BRC repeat.

Resumen

Different kinds of lesions can occur to DNA, and among them, one of the most dangerous is the double strand breaks (DSBs). Actually, DSBs can result in mutations, chromosome translocation or deletion. For this kind of lesions, depending on cell cycle phase as well as DNA-end resection, cells have developed specific repair pathways. Among these the error-free homologous recombination (HR) plays a crucial role. HR takes place during S/G2 phases, since the sister chromatids can be used as homologous templates. In this process, hRAD51 and BRCA2 are key players. hRAD51 is a recombinase of 339 amino-acids highly conserved through evolution which displays an intrinsic tendency to form oligomeric structures. BRCA2 is a very large protein of 3418 amino-acids, essential for the recruitment and accumulation of hRAD51 in the nucleus repairing-foci. BRCA2 interacts with hRAD51 through eight, so-called, BRC repeats, composed of 35-40 amino-acids. Mutations within this region have been linked to an increased risk of ovarian cancer development. In particular, several reports highlighted that missense mutations within one BRC repeat can hamper BRCA2 activity. Considering the close homology between the BRC repeats, it is striking how these mutations cannot be counterbalanced by the other non-mutated repeats preserving the function and the interactions of BRCA2 with hRAD51. To date the only interaction that has been structurally elucidated, is the one taking place amid the fourth BRC repeat and hRAD51. Only very little biophysical information is available on the interaction of the other BRC repeats with hRAD51. This thesis aims at elucidating the mechanism of hRAD51-BRCA2 interaction, by means of biophysical and structural approaches.

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