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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

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, Charlotte Kuperwasser

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. More... »

PAGES

7505

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms8505

DOI

http://dx.doi.org/10.1038/ncomms8505

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1050373754

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26106036


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