BRCA2encoded

The BRCA2-encoded protein is a tumor suppressor that plays a central role in the repair of DNA double-strand breaks by homologous recombination. The BRCA2 gene, located on chromosome 13 in humans, yields a large nuclear protein essential for genome stability. Pathogenic variants in BRCA2 increase lifetime risk for several cancers and, when present in both alleles, can cause Fanconi anemia type D1 in some cases.

The BRCA2 protein contains multiple functional regions, including BRC repeats that bind RAD51 and regulate filament formation, and a central DNA-binding domain with OB folds. It interacts with other DNA damage response factors such as PALB2 and BRCA1, and with the stabilizing partner DSS1. These interactions coordinate recruitment and assembly of the homologous recombination machinery at sites of damage.

Functionally, BRCA2 mediates the loading of RAD51 onto resected DNA ends, promoting strand invasion and accurate repair. It also contributes to replication fork protection, helping to stabilize stalled forks and limit degradation. BRCA2 participates in the broader Fanconi anemia pathway, linking crosslink repair with homologous recombination and maintaining genomic integrity during replication.

Clinical relevance is most evident in inherited cancer risk. Germline BRCA2 mutations elevate risks for breast, ovarian, prostate, and pancreatic cancers, among others. BRCA2 status informs risk assessment, surveillance, and management. Therapeutically, tumors with BRCA2 deficiency are sensitive to PARP inhibitors and certain platinum-based chemotherapies due to synthetic lethality, a principle that underpins targeted treatment strategies in BRCA2-mutant cancers.