Replication stress promotes cell elimination by extrusion
Author(s)
Dwivedi, Vivek Kumar; Pardo-Pastor, Carlos; Droste, Rita; Kong, Ji Na; Tucker, Nolan; Denning, Daniel Prudden; Rosenblatt, Jody; Horvitz, Howard Robert; ... Show more Show less
DownloadAccepted version (35.53Mb)
Publisher Policy
Publisher Policy
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Terms of use
Metadata
Show full item recordAbstract
Cell extrusion is a mechanism of cell elimination that is used by organisms as diverse as sponges, nematodes, insects and mammals1-3. 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 cancer1,5. 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 stress6,7 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.
Date issued
2021-05Department
Massachusetts Institute of Technology. Department of BiologyJournal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Dwivedi, Vivek K. et al. "Replication stress promotes cell elimination by extrusion." Nature 593, 7860 (May 2021): 591–596. © 2021 The Author(s)
Version: Author's final manuscript
ISSN
0028-0836
1476-4687