Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex

Muthana Al Abo, Donniphat Dejsuphong, Kouji Hirota, Yasukazu Yonetani, Mitsuyoshi Yamazoe, Hitoshi Kurumizaka, Shunichi Takeda

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    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 BRCA2DN mutant cells. Although previous studies have suggested that BRCA1-PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2DN 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 BRCA2DN that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DBD of BRCA2 in wild-type and BRCA2DN cells. Remarkably, although the resulting BRCA2DDBD cells displayed a moderate phenotype, the BRCA2DN+DDBD 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.

    Original languageEnglish
    Pages (from-to)797-807
    Number of pages11
    JournalCancer Research
    Volume74
    Issue number3
    DOIs
    Publication statusPublished - 2014 Feb 1

    Fingerprint

    DNA
    DNA Damage
    Phenotype
    BRCA2 Gene
    Camptothecin
    Null Lymphocytes
    Cisplatin
    Mutation
    Therapeutics
    Poly(ADP-ribose) Polymerase Inhibitors

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Al Abo, M., Dejsuphong, D., Hirota, K., Yonetani, Y., Yamazoe, M., Kurumizaka, H., & Takeda, S. (2014). Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. Cancer Research, 74(3), 797-807. https://doi.org/10.1158/0008-5472.CAN-13-1443

    Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. / Al Abo, Muthana; Dejsuphong, Donniphat; Hirota, Kouji; Yonetani, Yasukazu; Yamazoe, Mitsuyoshi; Kurumizaka, Hitoshi; Takeda, Shunichi.

    In: Cancer Research, Vol. 74, No. 3, 01.02.2014, p. 797-807.

    Research output: Contribution to journalArticle

    Al Abo, M, Dejsuphong, D, Hirota, K, Yonetani, Y, Yamazoe, M, Kurumizaka, H & Takeda, S 2014, 'Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex', Cancer Research, vol. 74, no. 3, pp. 797-807. https://doi.org/10.1158/0008-5472.CAN-13-1443
    Al Abo, Muthana ; Dejsuphong, Donniphat ; Hirota, Kouji ; Yonetani, Yasukazu ; Yamazoe, Mitsuyoshi ; Kurumizaka, Hitoshi ; Takeda, Shunichi. / Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. In: Cancer Research. 2014 ; Vol. 74, No. 3. pp. 797-807.
    @article{1db637f30e034840b663cb9477d87098,
    title = "Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex",
    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 BRCA2DN mutant cells. Although previous studies have suggested that BRCA1-PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2DN 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 BRCA2DN that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DBD of BRCA2 in wild-type and BRCA2DN cells. Remarkably, although the resulting BRCA2DDBD cells displayed a moderate phenotype, the BRCA2DN+DDBD 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.",
    author = "{Al Abo}, Muthana and Donniphat Dejsuphong and Kouji Hirota and Yasukazu Yonetani and Mitsuyoshi Yamazoe and Hitoshi Kurumizaka and Shunichi Takeda",
    year = "2014",
    month = "2",
    day = "1",
    doi = "10.1158/0008-5472.CAN-13-1443",
    language = "English",
    volume = "74",
    pages = "797--807",
    journal = "Journal of Cancer Research",
    issn = "0008-5472",
    publisher = "American Association for Cancer Research Inc.",
    number = "3",

    }

    TY - JOUR

    T1 - Compensatory functions and interdependency of the DNABinding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex

    AU - Al Abo, Muthana

    AU - Dejsuphong, Donniphat

    AU - Hirota, Kouji

    AU - Yonetani, Yasukazu

    AU - Yamazoe, Mitsuyoshi

    AU - Kurumizaka, Hitoshi

    AU - Takeda, Shunichi

    PY - 2014/2/1

    Y1 - 2014/2/1

    N2 - 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 BRCA2DN mutant cells. Although previous studies have suggested that BRCA1-PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2DN 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 BRCA2DN that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DBD of BRCA2 in wild-type and BRCA2DN cells. Remarkably, although the resulting BRCA2DDBD cells displayed a moderate phenotype, the BRCA2DN+DDBD 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.

    AB - 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 BRCA2DN mutant cells. Although previous studies have suggested that BRCA1-PALB2 plays a role in the recruitment of BRCA2 to DNA-damage sites, BRCA2DN 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 BRCA2DN that prevented stable interaction with PALB2. To test this hypothesis, we disrupted the DBD of BRCA2 in wild-type and BRCA2DN cells. Remarkably, although the resulting BRCA2DDBD cells displayed a moderate phenotype, the BRCA2DN+DDBD 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.

    UR - http://www.scopus.com/inward/record.url?scp=84893837418&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84893837418&partnerID=8YFLogxK

    U2 - 10.1158/0008-5472.CAN-13-1443

    DO - 10.1158/0008-5472.CAN-13-1443

    M3 - Article

    C2 - 24285729

    AN - SCOPUS:84893837418

    VL - 74

    SP - 797

    EP - 807

    JO - Journal of Cancer Research

    JF - Journal of Cancer Research

    SN - 0008-5472

    IS - 3

    ER -