BRCA2 stabilises RAD51 and DMC1 nucleoprotein filaments through a conserved interaction mode

Dunce, J.M., & Davies, O.R.

By Rayane Kaade

During cell division, DNA double-strand breaks (DSBs) can be repaired by the largely error-free mechanism of homologous recombination. In somatic cells, DSBs happen due to exogenous factors and upon replication fork collapse. DSBs can be restored through inter-sister recombination. In meiotic cells, endogenously induced DSBs trigger inter-homologue recombination, which is crucial for correct chromosome segregation and genetic diversity. Therefore, defects in homologous recombination are major contributors to genomic instability, cancer, and infertility.

The BRCA2 tumour suppressor plays a pivotal role in recombination by facilitating the loading of recombinases onto resected DNA ends to assemble nucleoprotein filaments. BRCA2 is known to interact with the RAD51 and DMC1 recombinases via its BRC repeats and PhePP motifs.BRCA2 has eight BRC repeats, which bind to RAD51 and DMC1 by converting their oligomers into monomers that are suitable for loading onto DNA. BRCA2 has also two PhePP motifs, in exon 14 and exon 27, which have divergent sequences and show specificity for DMC1 and RAD51 binding, respectively. PhePP motifs bind to filaments rather than monomers, so appear to cooperate with BRC repeats to form nucleoprotein filaments that are active in recombination. 

In this paper, James Dunce and Owen Davies determined the crystal structure of a BRCA2-DMC1 complex, revealing how Exon 14 PhePP motifs bind to oligomeric recombinases. Also, using electrophoretic mobility shift assays (EMSAs), they show that BRCA2 stabilises DMC1 nucleoprotein filaments. Finally, they show that BRCA2 Exon 27 binds to RAD51 through a conserved interaction mode. Hence, PhePP motifs protect nucleoprotein filaments, which then enable recombination in mitotic and meiotic cells, preventing chromosomal instability, cancer and meiotic impairment.