Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.

By N. Mccabe, N. Turner, C. Lord, Katarzyna Kluzek, A. Białkowska, S. Swift, Sabrina Giavara, Mark J. O'Connor, Andrew Tutt, M. Zdzienicka and 2 more. Cancer Research, 2006

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Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/40444578a0d316b415faba4654c2476521944776

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Citations in the corpus

DNA repair pathways as targets for cancer therapy (2008, background): “Cells that are defective in recombination-related proteins other than BRCA1 or BRCA2, such as RAD51 , RAD54, XRCC2 , XRCC3 , DSS1 (also known as SHFM1 ), replication protein A1 ( RPA1 ), ATM, ATR, CHK1, CHK2, NBS1 (also known as NBN ) and components of the Fanconi anaemia repair pathway, also s”
The DNA damage response and cancer therapy (2012, background): “As expected, most of these determinants cause PARP-inhibitor sensitivity by modulating homologous recombination (for example, RAD51, ATRX, SHFM1, RPA1, NBN, ATR, ATM, CHEK1, CHEK2, miR-182, CDK1, SWI5–SFR1, USP1/UAF1 and several Fanconi anaemia protein”
Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas (2013, positive): “In vitro studies demonstrate that deficiency in other homologous recombination proteins such as ATM, CHEK1, CHEK2, NBN, and RAD51D also confers sensitivity to PARPi (2, 13).”
PARP inhibition: PARP1 and beyond (2010, background): “Likewise, the observation that cells deficient in other crucial homologous recombination proteins are sensitive to PARP inhibitor”
Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Consistent with its major role in HR, BRCA2-deficient cells are sensitive to DNAdamaging agents that lead to lesions normally repaired by HR, including cross-linking agents 12 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a016600 (Kraakman-van der Zwet et al. 2002) and to PARP inhibitor”