Format

Send to

Choose Destination
Nat Commun. 2015 Jun 24;6:7505. doi: 10.1038/ncomms8505.

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

Author information

1
1] Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA [2] Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
2
Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
3
Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid E-28029, Spain.
4
Department of Cell Biology, Harvard Medical School and Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA.
5
Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
6
Department of Pathology, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts 02111, USA.
7
Department of Molecular Virology, Immunology, and Medical Genetics, Department of Internal Medicine's Division of Human Genetics, Ohio State University, Columbus, Ohio 43210, USA.
8
Molecular and Cellular Oncogenesis Program, The Wistar Institute, 36th and Spruce Sts. Philadelphia, Pennsylvania 19104, USA.

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 (BRCA1(mut/+)) 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.

PMID:
26106036
PMCID:
PMC4491827
DOI:
10.1038/ncomms8505
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center