Cell extrusion is a mechanism of cell elimination that is used by organisms as diverse as sponges, nematodes, insects and mammals^1,2,3. During extrusion, a cell detaches from a layer of surrounding cells while maintaining the continuity of that layer⁴. 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 Caenorhabditis elegans embryos³, 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.

细胞挤出是一种细胞消除机制，被海绵、线虫、昆虫和哺乳动物^1,2,3等多种生物使用。在挤压过程中，一个细胞从一层周围的细胞中分离出来，同时保持该层的连续性⁴。脊椎动物上皮组织主要通过挤压消除细胞，细胞挤压的失调与上皮疾病有关，包括癌症^1,5。驱动细胞挤压的机制仍未完全了解。在这里，分析秀丽隐杆线虫胚胎³的细胞挤压，我们进行了全基因组 RNA 干扰筛选，鉴定了多个具有 S 期特异性功能的细胞周期基因，并进行了实时成像实验以确定这些基因如何控制挤压。挤压细胞在 S 期经历复制应激，并通过 ATR 和 CHK1 的同源物激活复制应激反应。阻止 S 期进入、抑制复制应激反应或允许完成细胞周期阻止细胞挤出。羟基脲诱导的复制压力^6,7触发了哺乳动物上皮单层的 ATR-CHK1 和 p53 依赖性细胞挤出。我们得出结论，复制应激诱导的细胞挤出在动物中是保守的，并提出这种挤出过程是哺乳动物中具有肿瘤抑制功能的细胞消除的原始机制。