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Title: Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications
Authors: Philip, S.
Swaminathan, S. 
Kuznetsov, S.G.
Kanugula, S.
Biswas, K.
Chang, S.
Loktionova, N.A.
Haines, D.C.
Kaldis, P.
Pegg, A.E.
Sharan, S.K.
Issue Date: 1-Dec-2008
Citation: Philip, S., Swaminathan, S., Kuznetsov, S.G., Kanugula, S., Biswas, K., Chang, S., Loktionova, N.A., Haines, D.C., Kaldis, P., Pegg, A.E., Sharan, S.K. (2008-12-01). Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Research 68 (23) : 9973-9981. ScholarBank@NUS Repository.
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 O6-alkylguanine DNA alkyltransferase (AGT)-mediated repair of O6-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 O6-methylguanine adducts. We show that O6-benzylguanine (O6BG),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 O6BG 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. ©2008 American Association for Cancer Research.
Source Title: Cancer Research
ISSN: 00085472
DOI: 10.1158/0008-5472.CAN-08-1179
Appears in Collections:Staff Publications

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