Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition

McCabe, Nuala; Turner, Nicholas C.; Lord, Christopher J.; Kluzek, Katarzyna; Białkowska, Aneta; Swift, Sally; Giavara, Sabrina; O’Connor, Mark J.; Tutt, Andrew; Zdzienicka, Małgorzata Z.; Smith, Graeme C.M.; Ashworth, Alan

doi:10.1158/0008-5472.can-06-0140

Cited by 1,163 publications

(924 citation statements)

References 46 publications

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“…BRCA1 and BRCA2 mutant primary embryonic stem cells were each found to be highly sensitive to PARP inhibitors [102,103]. The same sensitivity is seen in a BRCA2 mutant tumor cell line, and in cells defective in other HR genes [104,105]. These findings are consistent with a defect in DSB repair at stalled/broken forks in BRCA mutant cells.…”

Section: Role Of Brca1 and Brca2 In Hr Regulationmentioning

confidence: 59%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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Section: Role Of Brca1 and Brca2 In Hr Regulationmentioning

confidence: 59%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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“…RHS1703; Open Biosystems, Huntsville, AL, USA). Tankyrasesilenced cells (HCT116-Tankyrase 1 shRNA) and control cells (HCT116-Control shRNA) were subsequently transfected with pSUPER shRNA constructs targeting either BRCA1 or BRCA2 (Figure 1b; Tutt et al, 2005;McCabe et al, 2006) and clonogenic survival assays were performed. Our results showed that inhibition of Tankyrase 1 was selectively lethal in cells with a reduction in either BRCA1 or BRCA2 expression, but had no effect in control cells (Figure 1c).…”

Section: Resultsmentioning

confidence: 99%

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

et al. 2009

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The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability and germ-line loss-offunction mutations in either BRCA1 or BRCA2 strongly predispose carriers to cancers of the breast and other organs. It has been demonstrated previously that inhibiting elements of the cellular DNA maintenance pathways represents a novel therapeutic approach to treating tumors in these individuals. Here, we show that inhibition of the telomere-associated protein, Tankyrase 1, is also selectively lethal with BRCA deficiency. We also demonstrate that the selectivity caused by inhibition of Tankyrase 1 is associated with an exacerbation of the centrosome amplification phenotype associated with BRCA deficiency. We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCAassociated cancers.

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“…The PARP1 inhibition disables such complementary repair mechanisms and renders cells particularly dependent on homologous recombination and therefore on BRCA1/2 function. Consequently, high sensitivity to PARP1 inhibitors is observed in BRCA1/2-deficient tumours (Bryant et al, 2005;Farmer et al, 2005), and enhanced sensitivity is also found in cells with impaired double-strand breaks signalling (McCabe et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

et al. 2007

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The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P ¼ 0.0003) and BRCA2 (30%; P ¼ 0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P ¼ 0.0002), progesterone receptor (PR) negative (P ¼ 0.004) and were of higher grade (P ¼ 0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P ¼ 0.0006) and p53 was overabundant (47%; Po0.0000000001) among the difficult-to-treat ER/PR/ ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

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Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition

Cited by 1,163 publications

References 46 publications

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

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