Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer

In humans, the interactions between the breast cancer susceptibility protein, BRCA2, and the RAD51 recombinase are essential for DNA repair by homologous recombination (HR), failure of which can predispose to cancer. The interactions occur through conserved BRC repeat motifs, encoded in BRCA2, binding directly to RAD51. Here, we describe full and partial BRCA2 homologues from a wide range of eukaryotes, including Drosophila melanogaster and two Plasmodium species. The crystal structure of the human BRC4-RAD51 complex allows identification of residues that are important for protein-protein interaction, and defines interaction sequence fingerprints for the BRC repeat and for RAD51. These allow us to predict that most eukaryotic RAD51 and BRC repeat orthologues should be capable of mutual interactions. We find no evidence for the presence of BRC repeats in yeast, Archaea and bacteria, and their RAD51 orthologues do not fulfil the criteria for binding the BRC repeat. Similarly, human RAD51 paralogues, including RAD51B, RAD51C, RAD51D, XRCC2, XRCC3 and DMC1, are not predicted to bind the BRC repeat. Conservation of the BRC repeat and RAD51 sequence fingerprints across a wide range of eukaryotic species substantiates the functional significance of the BRCA2-RAD51 interactions. The idea of multiple BRC repeats with binding specificity towards RAD51 leads us to suggest a possible model for the participation of BRCA2 in RAD51 nucleoprotein filament formation.