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BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine. / Jones, R.M.; Kotsantis, P.; Stewart, G.S. et al.
In: Molecular Cancer Therapeutics, Vol. 13, No. 10, 01.10.2014, p. 2412-421.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Jones, RM, Kotsantis, P, Stewart, GS, Groth, P & Petermann, E 2014, 'BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine', Molecular Cancer Therapeutics, vol. 13, no. 10, pp. 2412-421. https://doi.org/10.1158/1535-7163.MCT-13-0862

APA

Jones, R. M., Kotsantis, P., Stewart, G. S., Groth, P., & Petermann, E. (2014). BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine. Molecular Cancer Therapeutics, 13(10), 2412-421. https://doi.org/10.1158/1535-7163.MCT-13-0862

Vancouver

Jones RM, Kotsantis P, Stewart GS, Groth P, Petermann E. BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine. Molecular Cancer Therapeutics. 2014 Oct 1;13(10):2412-421. doi: 10.1158/1535-7163.MCT-13-0862

Author

Jones, R.M. ; Kotsantis, P. ; Stewart, G.S. et al. / BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 10. pp. 2412-421.

Bibtex

@article{aed2b10a482f4e85a8d74b3ed87357e1,
title = "BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine",
abstract = "Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors. ",
author = "R.M. Jones and P. Kotsantis and G.S. Stewart and P. Groth and E. Petermann",
year = "2014",
month = oct,
day = "1",
doi = "10.1158/1535-7163.MCT-13-0862",
language = "English",
volume = "13",
pages = "2412--421",
journal = "Molecular Cancer Therapeutics",
number = "10",

}

RIS

TY - JOUR

T1 - BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine

AU - Jones, R.M.

AU - Kotsantis, P.

AU - Stewart, G.S.

AU - Groth, P.

AU - Petermann, E.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors.

AB - Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors.

U2 - 10.1158/1535-7163.MCT-13-0862

DO - 10.1158/1535-7163.MCT-13-0862

M3 - Journal article

VL - 13

SP - 2412

EP - 2421

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 10

ER -