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Replication stress promotes cell elimination by extrusion.

Vivek K Dwivedi1, Carlos Pardo-Pastor2, Rita Droste1

  • 1Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

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Summary

Cell extrusion eliminates cells via replication stress, a conserved process across animals. This mechanism, involving ATR-CHK1 and p53, acts as a tumor suppressor in mammals.

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Area of Science:

  • Cell Biology
  • Developmental Biology
  • Genetics

Background:

  • Cell extrusion is a vital cell elimination process conserved across diverse organisms.
  • Dysregulation of cell extrusion is implicated in epithelial diseases, including cancer.
  • The precise molecular mechanisms driving cell extrusion are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms underlying cell extrusion.
  • To identify genes controlling cell extrusion using a genome-wide screen in *Caenorhabditis elegans*.
  • To determine the role of replication stress in cell extrusion.

Main Methods:

  • Conducted a genome-wide RNA interference screen in *Caenorhabditis elegans* embryos.
  • Performed live-imaging experiments to analyze cell extrusion dynamics.
  • Utilized hydroxyurea to induce replication stress in mammalian epithelial cells.

Main Results:

  • Identified cell-cycle genes with S-phase-specific functions crucial for extrusion.
  • Demonstrated that extruding cells experience and respond to replication stress via ATR and CHK1.
  • Showed that blocking S-phase entry or the replication stress response inhibits extrusion.
  • Induced extrusion in mammalian cells via hydroxyurea-induced replication stress, dependent on ATR-CHK1 and p53.

Conclusions:

  • Replication stress-induced cell extrusion is conserved across animal species.
  • This process is a primordial mechanism for cell elimination.
  • Cell extrusion mediated by replication stress may function as a tumor suppressor in mammals.