The breast cancer susceptibility proteins (BRCA) are required for reversed fork protection. (Top) Representative single-molecule DNA fiber images of DNA replication events labeled with the IdU (red) and CldU (green) thymidine analogs. Nucleases (blue packman) can degrade replication forks leading to a shortening of the labeled replication tracts. Scale bar, 15 µm. (Bottom) BRCA proteins protect reversed forks from nucleolytic degradation. In their absence, different nucleases (blue packman) promote reversed fork degradation.

Lemacon et. al,  Nat. Comm. 2017

Aside from their well-established roles in homologous recombination, BRCA proteins are emerging as key factors required for the maintenance of replication fork stability following chemotherapy. Both the homologous recombination defects and the pathological fork degradation of replication forks in BRCA-deficient cells have been linked to BRCA1-deficient cell sensitivity to agents that damage the DNA and that inhibit specific repair pathways, such PARP inhibitors. Importantly, when BRCA1-deficient cells acquire PARP inhibitor resistance, fork protection is restored in a BRCA1-independent manner. Our group is interested in elucidating the mechanisms that govern fork replication fork protection and recovery in cancer cells, and to understand how to target these mechanisms for the development of new and more effective cancer treatment strategies. To this end, we recently discovered that the main function of BRCA proteins in the context of fork protection is to protect the regressed arms of reversed replication forks from nucleolytic degradation upon drug treatment. We also discovered that extensive fork degradation in BRCA-deficient cells is not a terminal event, because BRCA-mutated cells employ specific fork recovery pathways as a last resort to withstand DNA-damaging chemotherapy. Collectively, these studies revisit the functions of central homologous recombination factors in DNA replication and are crucial to understanding how targeting fork recovery pathways can modulate current chemotherapeutic modalities.