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- Title
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
- Authors
Farmer, Hannah; McCabe, Nuala; Lord, Christopher J.; Tutt, Andrew N. J.; Johnson, Damian A.; Richardson, Tobias B.; Santarosa, Manuela; Dillon, Krystyna J.; Hickson, Ian; Knights, Charlotte; Martin, Niall M. B.; Jackson, Stephen P.; Smith, Graeme C. M.; Ashworth, Alan
- Abstract
BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
- Subjects
DNA repair; DNA damage; BIOCHEMICAL genetics; GENETIC mutation; CANCER genetics; APOPTOSIS
- Publication
Nature, 2005, Vol 434, Issue 7035, p917
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature03445