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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Externa organisationer
  • National Cancer Institute at Frederick
  • National University of Singapore
  • Pennsylvania State University College of Medicine
  • National Cancer Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)9973-9981
Antal sidor9
TidskriftCancer Research
Volym68
Utgåva nummer23
StatusPublished - 2008 dec 1
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa