TY - JOUR
T1 - Replication stress promotes cell elimination by extrusion
AU - Dwivedi, Vivek K
AU - Pardo-Pastor, Carlos
AU - Droste, Rita
AU - Kong, Ji Na
AU - Tucker, Nolan
AU - Denning, Daniel P
AU - Rosenblatt, Jody
AU - Horvitz, H Robert
N1 - Funding Information:
Acknowledgements We thank S. van den Heuvel and the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), for providing strains; L. Hufnagel and X. Trepat for providing MDCK-Fucci cells; G. van Meer and the ECACC for providing MDCK-II cells (ECACC 62107); N. An for strain management; S. Luo, S. R. Sando, E. L. Q. Lee, A. Doi, A. Corrionero and other members of the Horvitz laboratory for helpful discussions; and D. Ghosh, C. L. Pender, M. G. Vander Heiden, P. W. Reddien, and R. O. Hynes for suggestions regarding the manuscript. This work was supported by the Howard Hughes Medical Institute and by NIH grant R01GM024663. V.K.D. was a Howard Hughes Medical Institute International Student Research fellow. C.P.-P. was the recipient of Human Frontiers Science Program postdoctoral fellowship LT000654/2019-L. J.N.K. was supported by NIH grant R01GM024663. N.T. was supported by NIH Pre-Doctoral Training Grant T32GM007287. D.P.D. was supported by postdoctoral fellowships from the Damon Runyon Cancer Research Foundation and from the Charles A. King Trust. J.R. and C.P.-P. were funded by King’s College London startup funds. H.R.H. is the David H. Koch Professor of Biology at MIT and an Investigator at the Howard Hughes Medical Institute.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/27
Y1 - 2021/5/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105143727&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03526-y
DO - 10.1038/s41586-021-03526-y
M3 - Article
C2 - 33953402
AN - SCOPUS:85105143727
SN - 0028-0836
VL - 593
SP - 591
EP - 596
JO - Nature
JF - Nature
IS - 7860
ER -