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Supplementary Figure 4 from Compensatory Functions and Interdependency of the DNA-Binding Domain of BRCA2 with the BRCA1–PALB2–BRCA2 Complex

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posted on 2023-03-30, 22:20 authored by Muthana Al Abo, Donniphat Dejsuphong, Kouji Hirota, Yasukazu Yonetani, Mitsuyoshi Yamazoe, Hitoshi Kurumizaka, Shunichi Takeda

PDF file - 41K, Cellular sensitivity of the indicated BRCA2 mutant cells to the DNA-damaging agents.

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ARTICLE ABSTRACT

BRCA1, BRCA2, and PALB2 are key players in cellular tolerance to chemotherapeutic agents, including camptothecin, cisplatin, and PARP 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 BRCA2ΔN mutant cells. Although previous studies have suggested that BRCA1–PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2ΔN mutant cells displayed a considerably milder phenotype than did BRCA2−/− null-deficient cells. We hypothesized that the DNA-binding domain (DBD) of BRCA2 might compensate for a defect in BRCA2ΔN that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DBD of BRCA2 in wild-type and BRCA2ΔN cells. Remarkably, although the resulting BRCA2ΔDBD cells displayed a moderate phenotype, the BRCA2ΔN+ΔDBD cells displayed a very severe phenotype, as did the BRCA2−/− cells, suggesting that the N-terminal segment and the DBD 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 DBD 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 DBD 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 antimalignant therapies for patients carrying mutations in the BRCA2 gene. Cancer Res; 74(3); 797–807. ©2013 AACR.