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

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.This work was supported by grants from the Raymond and Beverly Sackler Foundation (M.S.), the Breast Cancer Research Foundation (B.K. and C.K.), the Silvian Foundation (C.K. and A.S.) and the NIH/NCI CA125554 (C.K.), CA092644 (C.K.). Research in the Blasco laboratory was funded by ERC Project Project TEL STEM CELL, FP7 Projects MARK-AGE and EuroBATS, Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, Regional of Government of Madrid Project S2010/BMD-2303, AXA Research Fund, Fundacion Botin (Spain) and Fundacion Lilly (Spain). We thank members of the Kuperwasser laboratory for valuable discussions as well as Benjamin Dake, Sarah Phillips and Agueda Tejera for their help with experiments.S