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Degradation of BRCA2 in Alkyltransferase-Mediated DNA Repair and Its Clinical Implications

  1. Author:
    Philip, S.
    Swaminathan, S.
    Kuznetsov, S. G.
    Kanugula, S.
    Biswas, K.
    Chang, S.
    Loktionova, N. A.
    Haines, D. C.
    Kaldis, P.
    Pegg, A. E.
    Sharant, S. K.

  2. Author Address

    Philip, Subha, Swaminathan, Srividya, Kuznetsov, Sergey G.; Biswas, Kajal, Chang, Suhwan, Kaldis, Philipp, Sharant, Shyam K.] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Haines, Diana C.] NCI, Sci Applicat Int Corp Frederick Inc, Pathol Histotechnol Lab, Frederick, MD 21702 USA. [Kanugula, Sreenivas, Loktionova, Natalia A.; Pegg, Anthony E.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA USA.
    1. Year: 2008
  2. Journal: Cancer Research
    1. 68
    2. 23
    3. Pages: 9973-9981
  4. Type of Article: Article
  1. Abstract:

    Germ-line mutations in BRCA2 have been linked to early-onset familial breast cancer. BRCA2 is known to play a key role in repairing double-strand breaks. Here, we describe the involvement of BRCA2 in O-6-alkylguanine DNA alkyltransferase (AGT)-mediated repair of O-6-methylguanine adducts. We show that BRCA2 physically associates and undergoes repair-mediated degradation with AGT. In contrast, BRCA2 with a 29-amino-acid deletion in an evolutionarily conserved domain does not bind to alkylated AGT, the two proteins are not degraded, and mouse embryonic fibroblasts are specifically sensitive to alkylating agents that result in O-6-methylguanine adducts. We show that O-6-benzylguanine (O(6)BG), a nontoxic inhibitor of AGT, can also induce BRCA2 degradation. BRCA2 is a viable target for cancer therapy because BRCA2-deficient cells are hypersensitive to chemotherapeutic DNA-damaging agents. We show a marked effect of O(6)BG pretreatment on cell sensitivity to cisplatin. We also show the efficacy of this approach on a wide range of human tumor cell lines, which suggests that chemosensitization of tumors by targeted degradation of BRCA2 may be an important consideration when devising cancer therapeutics. [Cancer Res 2008,68(23):9973-81]

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External Sources

  1. PMID: 19047179

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