| First Author | Philip S | Year | 2008 |
| Journal | Cancer Res | Volume | 68 |
| Issue | 23 | Pages | 9973-81 |
| PubMed ID | 19047179 | Mgi Jnum | J:142088 |
| Mgi Id | MGI:3820376 | Doi | 10.1158/0008-5472.CAN-08-1179 |
| Citation | Philip S, et al. (2008) Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Res 68(23):9973-81 |
| abstractText | 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. |
