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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cellular Senescence / genetics*
  • DNA Damage
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Genes, BRCA1*
  • Genomic Instability / genetics*
  • Haploinsufficiency*
  • Heterozygote
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism*
  • Mutation
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Telomere Shortening / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Retinoblastoma Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • SIRT1 protein, human
  • Sirtuin 1