Replication stress promotes cell elimination by extrusion
Name
DwivediEtAl.pdf
Description
Accepted version
Size
35.54 MB
Format
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Checksum (MD5)
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Author(s)
Dwivedi, Vivek Kumar
Pardo-Pastor, Carlos
Droste, Rita
Kong, Ji Na
Tucker, Nolan
Denning, Daniel Prudden
Rosenblatt, Jody
Horvitz, Howard Robert
Date Issued
May 2021
Journal
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
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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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.
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DOI of Published Version
https://doi.org/10.1038/s41586-021-03526-y
