TY - JOUR
T1 - Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications
AU - Philip, Subha
AU - Swaminathan, Srividya
AU - Kuznetsov, Sergey G.
AU - Kanugula, Sreenivas
AU - Biswas, Kajal
AU - Chang, Suhwan
AU - Loktionova, Natalia A.
AU - Haines, Diana C.
AU - Kaldis, Philipp
AU - Pegg, Anthony E.
AU - Sharan, Shyam K.
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=57149097470&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-1179
DO - 10.1158/0008-5472.CAN-08-1179
M3 - Article
C2 - 19047179
AN - SCOPUS:57149097470
SN - 0008-5472
VL - 68
SP - 9973
EP - 9981
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -