2026-06-14T03:42:20Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/100042024-11-29T13:41:53Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Sedic, Maja author Skibinski, Adam author Brown, Nelson author Gallardo, Mercedes author Mulligan, Peter author Martinez Rodriguez, Paula author Keller, Patricia J author Glover, Eugene author Richardson, Andrea L author Cowan, Janet author Toland, Amanda E author Ravichandran, Krithika author Riethman, Harold author Naber, Stephen P author Näär, Anders M author Blasco, MA author Hinds, Philip W author Kuperwasser, Charlotte author 2015-06-24 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. Nat Commun. 2015;6:7505. 10.1038/ncomms8505 2041-1723 2041-1723 Nature communications 26106036 http://hdl.handle.net/20.500.12105/10004 Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence