The Role of BRCA1 and BRCA2 in Anticancer Drug Therapy

Abstract

The genome is under constant assault from both endogenous and exogenous sources such as reactive oxygen species and ionizing radiation capable of inducing a wide array of mutagenic changes [1]. To maintain genomic integrity cells have evolved elegant mechanisms to recognize DNA damage, arrest the cell cycle, and activate specific repair pathways. One of the most cytotoxic lesions that a cell must contend with is a double-strand break (DSB) because even a single unrepaired DSB is capable of inducing cell death [2]. To repair a DSB, cells have at least four mechanisms at their disposal: homologous recombination (HR), single-strand annealing (SSA), nonhomologous end-joining (NHEJ), and microhomology-mediated end joining (MMEJ) (Fig. 1) [3]. HR relies on the sister chromatid as a template to fill in damaged or missing DNA, restoring the chromosome to its original condition. In cells with competent DNA repair mechanisms, HR is the preferred pathway of repair during the S and G2 phase of the cell cycle when the sister chromatid is available [4]. SSA, a variant of HR that is thought to play a minor role in the repair DSBs, utilizes homologous repeats surrounding a DSB to anneal the broken ends resulting in the deletion of the intervening sequence. In contrast, NHEJ and MMEJ both operate throughout the cell cycle and directly ligate two ends of a DSB; however, MMEJ always introduces small deletions at broken ends to produce a region of microhomology to facilitate ligation [5]. The important point to note is that HR is considered an error-free pathway whereas SSA, NHEJ, and MMEJ are error-prone because they can create gross chromosomal aberrations if ligation occurs incorrectly—potentially leading to neoplastic transformation [1].