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Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence

Author

Listed:
  • Maja Sedic

    (Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
    Molecular Oncology Research Institute, Tufts Medical Center)

  • Adam Skibinski

    (Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
    Molecular Oncology Research Institute, Tufts Medical Center)

  • Nelson Brown

    (Molecular Oncology Research Institute, Tufts Medical Center)

  • Mercedes Gallardo

    (Telomeres and Telomerase Group, Spanish National Cancer Centre)

  • Peter Mulligan

    (Harvard Medical School and Massachusetts General Hospital Cancer Center)

  • Paula Martinez

    (Telomeres and Telomerase Group, Spanish National Cancer Centre)

  • Patricia J. Keller

    (Molecular Oncology Research Institute, Tufts Medical Center)

  • Eugene Glover

    (Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
    Molecular Oncology Research Institute, Tufts Medical Center)

  • Andrea L. Richardson

    (Harvard Medical School, Brigham and Women’s Hospital)

  • Janet Cowan

    (Tufts Medical Center)

  • Amanda E. Toland

    (Immunology, and Medical Genetics, Ohio State University)

  • Krithika Ravichandran

    (Molecular and Cellular Oncogenesis Program, The Wistar Institute)

  • Harold Riethman

    (Molecular and Cellular Oncogenesis Program, The Wistar Institute)

  • Stephen P. Naber

    (Tufts Medical Center)

  • Anders M. Näär

    (Harvard Medical School and Massachusetts General Hospital Cancer Center)

  • Maria A. Blasco

    (Telomeres and Telomerase Group, Spanish National Cancer Centre)

  • Philip W. Hinds

    (Molecular Oncology Research Institute, Tufts Medical Center)

  • Charlotte Kuperwasser

    (Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
    Molecular Oncology Research Institute, Tufts Medical Center)

Abstract

Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1mut/+) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.

Suggested Citation

  • Maja Sedic & Adam Skibinski & Nelson Brown & Mercedes Gallardo & Peter Mulligan & Paula Martinez & Patricia J. Keller & Eugene Glover & Andrea L. Richardson & Janet Cowan & Amanda E. Toland & Krithika, 2015. "Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8505
    DOI: 10.1038/ncomms8505
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