Replication stress promotes cell elimination by extrusion

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.