title: Immortalised breast epithelia survive prolonged DNA replication stress and return to cycle from a senescent-like state.
abstract: Mammalian cells have mechanisms to counteract the effects of metabolic and exogenous stresses, many of that would be mutagenic if ignored. Damage arising during DNA replication is a major source of mutagenesis. The extent of damage dictates whether cells undergo transient cell cycle arrest and damage repair, senescence or apoptosis. Existing dogma defines these alternative fates as distinct choices. Here we show that immortalised breast epithelial cells are able to survive prolonged S phase arrest and subsequently re-enter cycle after many days of being in an arrested, senescence-like state. Prolonged cell cycle inhibition in fibroblasts induced DNA damage response and cell death. However, in immortalised breast epithelia, efficient S phase arrest minimised chromosome damage and protected sufficient chromatin-bound replication licensing complexes to allow cell cycle re-entry. We propose that our observation could have implications for the design of drug therapies for breast cancer.
authors: 1] Faculty of Life Sciences and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK [2] Genome Integrity Unit, Danish Cancer Society Research Centre, Copenhagen, Denmark.
authors: A
authors: A
authors: Maya-Mendoza
authors: Genome Integrity Unit, Danish Cancer Society Research Centre, Copenhagen, Denmark.
authors: J M
authors: JM
authors: Merchut-Maya
authors: Genome Integrity Unit, Danish Cancer Society Research Centre, Copenhagen, Denmark.
authors: J
authors: J
authors: Bartkova
authors: 1] Genome Integrity Unit, Danish Cancer Society Research Centre, Copenhagen, Denmark [2] Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-779 00 Olomouc, Czech Republic.
authors: J
authors: J
authors: Bartek
authors: Faculty of Life Sciences and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: C H
authors: CH
authors: Streuli
authors: Faculty of Life Sciences and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: D A
authors: DA
authors: Jackson
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D004249:DNA Damage; D004261:DNA Replication; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D016196:S Phase