Compensatory functions and interdependency of the DNA-binding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex.

Cancer Research

PubMedID: 24285729

Al Abo M, Dejsuphong D, Hirota K, Yonetani Y, Yamazoe M, Kurumizaka H, Takeda S. Compensatory functions and interdependency of the DNA-binding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. Cancer Res. 2014;74(3):797-807.
BRCA1, BRCA2 and PALB2 are key players in cellular tolerance to chemotherapeutic agents including camptothecin, cisplatin and poly[ADP ribose]polymerase inhibitor. The N-terminal segment of BRCA2 interacts with PALB2, thus contributing to the formation of the BRCA1-PALB2-BRCA2 complex. To understand the role played by BRCA2 in this complex, we deleted its N-terminal segment and generated BRCA2N mutant cells. Although previous studies have suggested that BRCA1-PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2N mutant cells displayed a considerably milder phenotype than did BRCA2-/- null-deficient cells. We hypothesized that the DNA-binding domain of BRCA2 might compensate for a defect in BRCA2N that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DNA-binding domain of BRCA2 in wild-type and BRCA2N cells. Remarkably, although the resulting BRCA2DBD cells displayed a moderate phenotype, the BRCA2N+DBD cells displayed a very severe phenotype, as did the BRCA2-/- cells, suggesting that the N-terminal segment and the DNA-binding domain play a substantially overlapping role in the functionality of BRCA2. We also showed that the formation of both the BRCA1-PALB2-BRCA2 complex and the DNA-binding domain is required for efficient recruitment of BRCA2 to DNA-damage sites. Our study revealed the essential role played by both the BRCA1-PALB2-BRCA2 complex and the DNA-binding domain in the functionality of BRCA2, as each can compensate for the other in the recruitment of BRCA2 to DNA-damage sites. This knowledge adds to our ability to accurately predict the efficacy of anti-malignant therapies for patients carrying mutations in the BRCA2 gene.