Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

Hannah Farmer, Huala McCabe, Christopher J. Lord, Andrew H J Tutt, Damian A. Johnson, Tobias B. Richardson, Manuela Santarosa, Krystyna J. Dillon, Ian Hickson, Charlotte Knights, Niall M B Martin, Stephen P. Jackson, Graeme C M Smith, Alan Ashworth

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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.

Original languageEnglish
Pages (from-to)917-921
Number of pages5
JournalNature
Volume434
Issue number7035
DOIs
Publication statusPublished - Apr 14 2005

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Cite this

Farmer, H., McCabe, H., Lord, C. J., Tutt, A. H. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M. B., Jackson, S. P., Smith, G. C. M., & Ashworth, A. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434(7035), 917-921. https://doi.org/10.1038/nature03445