BRC4wt is a peptide derived from the BRC4 repeat motif of the BReast CAncer gene 2 (BRCA2) protein, which is able to prevent the DNA repair protein RAD51 binding to BRCA2. Cancer cells rely on efficient DNA repair to survive and proliferate and the BRCA2 tumour suppressor protein is indispensable for repair of DNA double-strand breaks through promotion of RAD51 loading onto single-stranded DNA. Through blockade of this interaction BRC4wt inhibits camptothecin and ionising radiation induced RAD51 foci formation and homologous recombination in cancer cells. BRC4wt can impair the replication fork-protective function of BRCA2 and trigger double-strand break repair protein MRE11 dependent degradation of nascent DNA in response to replication stress. A BRC4wt cell penetrating peptide derivative confers selective hypersensitivity to PARP inhibition in cancer cells but spares noncancerous cells, giving it potential as a radio and chemosensitiser.
