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

@article{Farmer2005TargetingTD,
  title={Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy},
  author={Hannah Farmer and N. Mccabe and Christopher J. Lord and Andrew N.J. Tutt and Damian A. Johnson and T B Richardson and Manuela Santarosa and Krystyna J. Dillon and Ian D. Hickson and Charlotte Knights and Niall M. B. Martin and Stephen P. Jackson and Graeme C M Smith and Alan Ashworth},
  journal={Nature},
  year={2005},
  volume={434},
  pages={917-921}
}
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. [...] Key Result 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.Expand

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References

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TLDR
It is proposed that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage. Expand
Brca1 controls homology-directed DNA repair.
TLDR
A caretaker role for BRCA1 is demonstrated in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes. Expand
The relationship between the roles of BRCA genes in DNA repair and cancer predisposition.
TLDR
It appears that the role of BRCA1 in DNA repair, which could involve the integration of several pathways, is broader than that of B RCA2. Expand
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
TLDR
It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone. Expand
Involvement of poly(ADP-ribose) polymerase in base excision repair.
TLDR
PARP knockout mice and the derived mouse embryonic fibroblasts were acutely sensitive to monofunctional alkylating agents and gamma-irradiation demonstrating that PARP is involved in recovery from DNA damage that triggers the base excision repair (BER) process. Expand
Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein.
TLDR
It is proposed that in BRCA2 deficiency and related chromosomal instability diseases, the breakdown of replication forks, which arrest or pause during normal cell growth, triggers spontaneous DNA breakage, leading to mutability and cancer predisposition. Expand
Mutation in Brca2 stimulates error‐prone homology‐directed repair of DNA double‐strand breaks occurring between repeated sequences
TLDR
It is shown that loss of Brca2 leads to a substantial increase in error‐prone repair by homology‐directed single‐strand annealing and a reduction in DSB repair by conservative gene conversion, and provides insight into the mechanisms that induce genome instability in tumour cells lacking BRCA2. Expand
Brca2 (XRCC11) Deficiency Results in Radioresistant DNA Synthesis and a Higher Frequency of Spontaneous Deletions
TLDR
It is shown that the radiosensitive Chinese hamster cell mutant (V-C8) of group XRCC11 is defective in the breast cancer susceptibility gene Brca2, which causes hypersensitivity to various DNA-damaging agents with an extreme sensitivity toward interstrand DNA cross-linking agents. Expand
PARP is important for genomic stability but dispensable in apoptosis.
TLDR
Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor alpha, gamma-irradiation, and dexamethasone, indicating thatPARP is dispensable in apoptosis and that PARP-/- thymocytes are not hypersensitive to ionizing radiation. Expand
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  • Biology, Medicine
  • Trends in biochemical sciences
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TLDR
This work has shown that gene conversion and break-induced replication are related processes that both begin with the establishment of a replication fork in which both leading- and lagging-strand synthesis occur. Expand
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