Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/10004
Título
Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence
Autor(es)
Sedic, Maja | Skibinski, Adam | Brown, Nelson | Gallardo, Mercedes | Mulligan, Peter | Martinez Rodriguez, Paula CNIO | Keller, Patricia J | Glover, Eugene | Richardson, Andrea L | Cowan, Janet | Toland, Amanda E | Ravichandran, Krithika | Riethman, Harold | Naber, Stephen P | Näär, Anders M | Blasco, MA CNIO | Hinds, Philip W | Kuperwasser, Charlotte
Fecha de publicación
2015-06-24
Cita
Nat Commun. 2015;6:7505.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Cellular Senescence | DNA Damage | Epithelial Cells | Genomic Instability | Heterozygote | Humans | Mammary Glands, Human | Mutation | Retinoblastoma Protein | Sirtuin 1 | Telomere Shortening | Tumor Suppressor Protein p53 | Genes, BRCA1 | Haploinsufficiency
Versión en línea
DOI
Aparece en las colecciones