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Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications

Philip, Subha ; Swaminathan, Srividya ; Kuznetsov, Sergey G. ; Kanugula, Sreenivas ; Biswas, Kajal ; Chang, Suhwan ; Loktionova, Natalia A. ; Haines, Diana C. ; Kaldis, Philipp LU orcid and Pegg, Anthony E. , et al. (2008) In Cancer Research 68(23). p.9973-9981
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
68
issue
23
pages
9 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:57149097470
  • pmid:19047179
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-08-1179
language
English
LU publication?
no
id
0908955f-9b12-4365-aba5-5ecdeda15150
date added to LUP
2019-09-18 14:12:18
date last changed
2024-02-15 21:50:36
@article{0908955f-9b12-4365-aba5-5ecdeda15150,
  abstract     = {{<p>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<sup>6</sup>-alkylguanine DNA alkyltransferase (AGT)-mediated repair of O<sup>6</sup>-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<sup>6</sup>-methylguanine adducts. We show that O<sup>6</sup>-benzylguanine (O<sup>6</sup>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<sup>6</sup>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.</p>}},
  author       = {{Philip, Subha and Swaminathan, Srividya and Kuznetsov, Sergey G. and Kanugula, Sreenivas and Biswas, Kajal and Chang, Suhwan and Loktionova, Natalia A. and Haines, Diana C. and Kaldis, Philipp and Pegg, Anthony E. and Sharan, Shyam K.}},
  issn         = {{0008-5472}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{23}},
  pages        = {{9973--9981}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-08-1179}},
  doi          = {{10.1158/0008-5472.CAN-08-1179}},
  volume       = {{68}},
  year         = {{2008}},
}