Discovered in the 1990s, the BRCA1 and BRCA2 genes are now recognized as quintessential tumor suppressor genes, whose mutations are major risk factors for developing breast cancer, ovarian cancer, and several other malignancies [1], [2], [3], [4], [5], [6]. These genes play pivotal roles in preserving genomic stability, particularly in response to damage caused by byproducts of cellular metabolism as well as physical, chemical, and environmental stressors. To counteract such internal and external threats, cells activate sophisticated DNA damage response (DDR) pathways that safeguard genomic integrity [7], [8], [9], [10], [11], [12], [13], [14]. Among the various forms of DNA damage, double-strand breaks (DSBs) pose the greatest threat to DNA’s structural integrity. BRCA1 and BRCA2 are integral to the repair of DSBs through homologous recombination (HR), one of the two primary DSB repair mechanisms—the other being non-homologous end joining (NHEJ)[15], [16], [17], [18], [19], [20]. Beyond their roles in DSB repair, BRCA1 and BRCA2 are critical in responding to replication stress, which can arise from a range of factors that stall replication forks. Cells rely on the DNA damage tolerance (DDT) pathway to overcome these replication obstacles [21], [22]. BRCA1 and BRCA2 play essential roles in stabilizing stalled replication forks and orchestrating the replication stress response.

The concept of synthetic lethality associated with BRCA1 and BRCA2 mutations has revolutionized the field of cancer therapy. Poly (ADP-ribose) polymerase inhibitors (PARPi) target the base excision repair (BER) pathway, converting single-strand breaks (SSBs) into DSBs, which require HR for repair [9], [23], [24]. Tumor cells deficient in BRCA1 or BRCA2 lack the ability to perform HR, rendering them highly sensitive to PARPi. This selective vulnerability enables PARPi to induce irreparable DNA damage, leading to tumor cell death [9], [25], [26], [27]. By exploiting this dependency, PARPi-based therapies have significantly improved outcomes for patients with BRCA-mutant cancers, exemplifying the potential of precision medicine in combating malignancies.

BRCA1 and BRCA2 are known to interact with various protein complexes, playing crucial roles in DDR and stalled fork protection (Fig. 1). This review synthesizes recent advances in our understanding of BRCA1 and BRCA2 functions, aiming to shed light on their roles in DDR, replication stress response, and cancer therapy, while providing directions for future research.