Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence
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Author
Sedic, Maja
Skibinski, Adam
Brown, Nelson
Gallardo, Mercedes
Mulligan, Peter
Martinez, Paula
Keller, Patricia J.
Glover, Eugene
Cowan, Janet
Toland, Amanda E.
Ravichandran, Krithika
Riethman, Harold
Naber, Stephen P.
Blasco, Maria A.
Hinds, Philip W.
Kuperwasser, Charlotte
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ncomms8505Metadata
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Sedic, M., A. Skibinski, N. Brown, M. Gallardo, P. Mulligan, P. Martinez, P. J. Keller, et al. 2015. “Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence.” Nature Communications 6 (1): 7505. doi:10.1038/ncomms8505. http://dx.doi.org/10.1038/ncomms8505.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491827/pdf/Terms of Use
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