Replication stress promotes cell elimination by extrusion

Cell extrusion is a mechanism of cell elimination that is used by organisms as diverse as sponges, nematodes, insects and mammals(1-3). During extrusion, a cell detaches from a layer of surrounding cells while maintaining the continuity of that layer(4). Vertebrate epithelial tissues primarily eliminate cells by extrusion, and the dysregulation of cell extrusion has been linked to epithelial diseases, including cancer(1,5). The mechanisms that drive cell extrusion remain incompletely understood. Here, to analyse cell extrusion by Caenorhabdids elegans embryos(3), we conducted a genome-wide RNA interference screen, identified multiple cell-cycle genes with S-phase-specific function, and performed live-imaging experiments to establish how those genes control extrusion. Extruding cells experience replication stress during S phase and activate a replication-stress response via homologues of ATR and CHK1. Preventing S-phase entry, inhibiting the replication-stress response, or allowing completion of the cell cycle blocked cell extrusion. Hydroxyurea-induced replication stress(6,7) triggered ATR-CHK1- and p53-dependent cell extrusion from a mammalian epithelial monolayer. We conclude that cell extrusion induced by replication stress is conserved among animals and propose that this extrusion process is a primordial mechanism of cell elimination with a tumour-suppressive function in mammals.

Automated summary

Cell extrusion is a mechanism of cell elimination utilized by various organisms. Through a genome-wide RNA interference screen, S-phase specific cell cycle genes were identified to play a role in the extrusion process. Cells experiencing replication stress in S-phase activate a replication-stress response, leading to cell extrusion. This mechanism is conserved across different species.