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

Subha Philip, Srividya Swaminathan, Sergey G. Kuznetsov, Sreenivas Kanugula, Kajal Biswas, Suhwan Chang, Natalia A. Loktionova, Diana C. Haines, Philipp Kaldis, Anthony E. Pegg, Shyam K. Sharan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)9973-9981
Number of pages9
JournalCancer Research
Volume68
Issue number23
DOIs
StatePublished - Dec 1 2008

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Alkyl and Aryl Transferases
DNA Repair
Neoplasms
Germ-Line Mutation
Alkylating Agents
Tumor Cell Line
Cisplatin
Fibroblasts
Amino Acids
DNA
Therapeutics
Proteins
O-(6)-methylguanine
O(6)-benzylguanine

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Philip, S., Swaminathan, S., Kuznetsov, S. G., Kanugula, S., Biswas, K., Chang, S., ... Sharan, S. K. (2008). Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Research, 68(23), 9973-9981. https://doi.org/10.1158/0008-5472.CAN-08-1179
Philip, Subha ; Swaminathan, Srividya ; Kuznetsov, Sergey G. ; Kanugula, Sreenivas ; Biswas, Kajal ; Chang, Suhwan ; Loktionova, Natalia A. ; Haines, Diana C. ; Kaldis, Philipp ; Pegg, Anthony E. ; Sharan, Shyam K. / Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. In: Cancer Research. 2008 ; Vol. 68, No. 23. pp. 9973-9981.
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Philip, S, Swaminathan, S, Kuznetsov, SG, Kanugula, S, Biswas, K, Chang, S, Loktionova, NA, Haines, DC, Kaldis, P, Pegg, AE & Sharan, SK 2008, 'Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications', Cancer Research, vol. 68, no. 23, pp. 9973-9981. https://doi.org/10.1158/0008-5472.CAN-08-1179

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; Pegg, Anthony E.; Sharan, Shyam K.

In: Cancer Research, Vol. 68, No. 23, 01.12.2008, p. 9973-9981.

Research output: Contribution to journalArticle

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AU - Philip, Subha

AU - Swaminathan, Srividya

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AU - Chang, Suhwan

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AU - Haines, Diana C.

AU - Kaldis, Philipp

AU - Pegg, Anthony E.

AU - Sharan, Shyam K.

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Philip S, Swaminathan S, Kuznetsov SG, Kanugula S, Biswas K, Chang S et al. Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Research. 2008 Dec 1;68(23):9973-9981. https://doi.org/10.1158/0008-5472.CAN-08-1179