Dynamic stem cell selection safeguards the genomic integrity of the epidermis- Kato et al

Maintaining genomic integrity and stability is crucial for life, yet no tissue-driven mechanism that robustly safeguards the epithelial genome has been discovered. Epidermal stem cells (EpiSCs) continuously replenish the stratified layers of keratinocytes that protect organisms against various environmental stresses. To study the dynamics of DNA-damaged cells in tissues, we devised an in vivo fate tracing system for EpiSCs with DNA double-strand breaks (DSBs) and demonstrate that those cells exit from their niche. The clearance of EpiSCs with DSBs is caused by selective differentiation and delamination through the DNA damage response (DDR)-p53-Notch axis with the downregulation of ITGB1. Moreover, concomitant enhancement of symmetric cell divisions of surrounding stem cells indicates that the selective elimination of cells with DSBs is coupled with the augmented clonal expansion of intact stem cells. These data collectively demonstrate that the dynamic coupling of cell-autonomous and non-cell-autonomous mechanisms coordinately maintains the genomic quality of the epidermis.