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

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 Ravichandran, Harold Riethman, Stephen P. Naber, Anders M. Näär, Maria A. Blasco, Philip W. Hinds and Charlotte Kuperwasser ()
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Maja Sedic: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
Adam Skibinski: Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8505

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