Patients who lack functional BRCA proteins are at increased risk of developing breast cancer owing to the essential role that these proteins have in DNA repair. Three recent publications in Nature have highlighted how BRCA2 functions to regulate DNA repair and how this functional deficit in cancer cells can be exploited therapeutically.

Stephen West and colleagues investigated the interaction between BRCA2 and RAD51. RAD51 is a crucial component of the homologous recombination (HR) repair pathway and interacts with BRCA2 through the BRCA2 BRC-repeat motifs and through an interaction domain in the carboxyl terminus. Current data indicate that this interaction facilitates two essential processes: the formation of RAD51 nucleoprotein filaments, which are essential for RAD51 recombinase activity, and the rapid association of RAD51 with sites of DNA damage. West and colleagues used a series of tagged protein fragments from the C-terminus of BRCA2 to determine the RAD51-interaction motif. They found that phosphorylation of Ser3291 in the C-terminus of BRCA2 regulates the interaction with RAD51. Phosphorylation of this residue is carried out by cyclin-dependent kinases (CDKs) in the G2/M phase of the cell cycle. Furthermore, CDK-dependent phosphorylation was inhibited after DNA damage, facilitating the interaction between RAD51 and the BRCA2 C-terminus and the localization of RAD51 to DNA-damage foci. These findings indicate that BRCA2 Ser3291 phosphorylation regulates the activity of RAD51, preventing its recombinase activity during G2/M but facilitating the repair of any replication-induced strand breaks during S-phase.

Importantly, evidence from human breast cancers indicates that the region around Ser3291 is a mutational hot spot. Loss of the C-terminal portion of BRCA2, but retention of the BRC domains, results in an impaired response to ionizing radiation — RAD51-focus formation is lost and repair of DNA damage through HR is disrupted. Although the isolation of this phosphorylation site might indicate potential strategies for therapeutic intervention, two other papers indicate that tumours that lack BRCA2 (or BRCA1) can be targeted precisely because they cannot carry out HR effectively.

Thomas Helleday and colleagues, and Alan Ashworth and colleagues demonstrate that inhibiting the DNA-repair enzyme poly(ADP)ribose polymerase (PARP) increases the formation of RAD51-repair foci. Previous findings indicate that PARP1 has no direct function in HR, but that the absence of PARP1 increases the need for effective HR repair pathways. The teams both reasoned that spontaneously occurring single-stranded DNA breaks are not repaired effectively in PARP1-deficient cells and these breaks are likely to be converted into double-stranded DNA breaks during replication, resulting in collapsed replication forks. Normally, BRCA2 would recruit RAD51 to these sites to carry out HR, but in the absence of functional BRCA2 (and BRCA1, as Ashworth and colleagues show), HR does not occur, prompting the use of error-prone DNA-repair pathways with lethal consequences for the cell.

Helleday and Ashworth also show in their respective papers that the differential sensitivity of BRCA2−/− cells to PARP inhibitors is extremely high. So patients who are heterozygous for either BRCA1 or BRCA2 might benefit from a PARP-based treatment strategy, as the tumours arising in these patients are BRCA-null, but the rest of the patients' cells remain heterozygous and therefore unaffected by PARP inhibition. Indeed, the Helleday group suggest that the low toxicity of PARP inhibitors indicates their potential as preventive treatments for BRCA hereditary breast cancer. In addition, as Ashworth and colleagues point out, this work also implies that any tumours with defects within the HR pathway (that is, exhibiting 'BRCAness') might be treatable through inhibiting the function of PARP1.