{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Sedic M"],"funding":["NHGRI NIH HHS","NCI NIH HHS"],"pagination":["7505"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4491827"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6"],"pubmed_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 telom"],"journal":["Nature communications"],"pubmed_title":["Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence."],"pmcid":["PMC4491827"],"funding_grant_id":["P01 CA092644","CA125554","R01 CA125554","P30 CA010815","R21 HG007205","R21 CA177395","CA092644"],"pubmed_authors":["Mulligan P","Keller PJ","Cowan J","Toland AE","Hinds PW","Riethman H","Sedic M","Martinez P","Gallardo M","Blasco MA","Ravichandran K","Glover E","Brown N","Kuperwasser C","Naber SP","Skibinski A","Richardson AL","Naar AM"],"additional_accession":[]},"is_claimable":false,"name":"Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence.","description":"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 telom","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015 Jun","modification":"2026-05-01T14:49:23.443Z","creation":"2019-03-27T01:54:34Z"},"accession":"S-EPMC4491827","cross_references":{"pubmed":["26106036"],"doi":["10.1038/ncomms8505"]}}