Loss of Slug Compromises DNA Damage Repair and Accelerates Stem Cell Aging in Mammary Epithelium

摘要

DNA damage activates checkpoints that limit thereplicative potential of stem cells, including differentiation.These checkpoints protect against cancerdevelopment but also promote tissue aging.Because mice lacking Slug/Snai2 exhibit limitedstem cell activity, including luminobasal differentiation,and are protected from mammary cancer, wereasoned that Slug might regulate DNA damagecheckpoints in mammary epithelial cells. Here, weshow that Slug facilitates efficient execution ofRPA32-mediated DNA damage response (DDR)signaling. Slug deficiency leads to delayed phosphorylationof ataxia telangiectasia mutated andRad3-related protein (ATR) and its effectors RPA32and CHK1. This leads to impaired RAD51 recruitmentto DNA damage sites and persistence of unresolvedDNA damage. In vivo, Slug/Snai2 loss leads toincreased DNA damage and premature aging ofmammary epithelium. Collectively, our work demonstratesthat the mammary stem cell regulator Slugcontrols DDR checkpoints by dually inhibiting differentiationand facilitating DDR repair, and its losscauses unresolved DNA damage and acceleratedaging.