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Replication stress promotes cell elimination by extrusion

Author

Listed:
  • Vivek K. Dwivedi

    (Massachusetts Institute of Technology)

  • Carlos Pardo-Pastor

    (King’s College London)

  • Rita Droste

    (Massachusetts Institute of Technology)

  • Ji Na Kong

    (Massachusetts Institute of Technology)

  • Nolan Tucker

    (Massachusetts Institute of Technology)

  • Daniel P. Denning

    (Massachusetts Institute of Technology
    Novartis Institutes for BioMedical Research)

  • Jody Rosenblatt

    (King’s College London)

  • H. Robert Horvitz

    (Massachusetts Institute of Technology)

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.

Suggested Citation

  • Vivek K. Dwivedi & Carlos Pardo-Pastor & Rita Droste & Ji Na Kong & Nolan Tucker & Daniel P. Denning & Jody Rosenblatt & H. Robert Horvitz, 2021. "Replication stress promotes cell elimination by extrusion," Nature, Nature, vol. 593(7860), pages 591-596, May.
    • Handle: RePEc:nat:nature:v:593:y:2021:i:7860:d:10.1038_s41586-021-03526-y
    DOI: 10.1038/s41586-021-03526-y
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    Cited by:

    1. John Fadul & Teresa Zulueta-Coarasa & Gloria M. Slattum & Nadja M. Redd & Mauricio Franco Jin & Michael J. Redd & Stephan Daetwyler & Danielle Hedeen & Jan Huisken & Jody Rosenblatt, 2021. "KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Michael E. Baumgartner & Paul F. Langton & Remi Logeay & Alex Mastrogiannopoulos & Anna Nilsson-Takeuchi & Iwo Kucinski & Jules Lavalou & Eugenia Piddini, 2023. "The PECAn image and statistical analysis pipeline identifies Minute cell competition genes and features," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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