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BRCA1 haploinsufficiency for replication stress suppression in primary cells

Author

Listed:
  • Shailja Pathania

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Sangeeta Bade

    (Dana-Farber Cancer Institute)

  • Morwenna Le Guillou

    (Stabilité Génétique et Oncogenèse, Université Paris-Sud, CNRS-UMR8200, Gustave-Roussy)

  • Karly Burke

    (Harvard Medical School)

  • Rachel Reed

    (Dana-Farber Cancer Institute)

  • Christian Bowman-Colin

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Ying Su

    (Dana-Farber Cancer Institute)

  • David T. Ting

    (Harvard Medical School
    Massachusetts General Hospital)

  • Kornelia Polyak

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Andrea L. Richardson

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St)

  • Jean Feunteun

    (Stabilité Génétique et Oncogenèse, Université Paris-Sud, CNRS-UMR8200, Gustave-Roussy)

  • Judy E. Garber

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • David M. Livingston

    (Harvard Medical School
    Dana-Farber Cancer Institute)

Abstract

BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.

Suggested Citation

  • Shailja Pathania & Sangeeta Bade & Morwenna Le Guillou & Karly Burke & Rachel Reed & Christian Bowman-Colin & Ying Su & David T. Ting & Kornelia Polyak & Andrea L. Richardson & Jean Feunteun & Judy E., 2014. "BRCA1 haploinsufficiency for replication stress suppression in primary cells," Nature Communications, Nature, vol. 5(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6496
    DOI: 10.1038/ncomms6496
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    Cited by:

    1. Kevin Elias & Urszula Smyczynska & Konrad Stawiski & Zuzanna Nowicka & James Webber & Jakub Kaplan & Charles Landen & Jan Lubinski & Asima Mukhopadhyay & Dona Chakraborty & Denise C. Connolly & Heathe, 2023. "Identification of BRCA1/2 mutation female carriers using circulating microRNA profiles," Nature Communications, Nature, vol. 14(1), pages 1-9, December.

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