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Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival

Lina Guerra1, Riccardo Guidi, Ilse Slot

  • 1Department of Cell and Molecular Biology, Karolinska Institutet, Box 285, S-171 77 Stockholm, Sweden.

Journal of Cell Science
|August 3, 2011
PubMed

Insights

Bacterial toxins trigger DNA damage responses that activate RhoA and MAPK p38, promoting cell survival. A screen identified FEN1 as crucial for this response, linking DNA repair and cytoskeleton dynamics.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Microbiology

Background:

  • Bacterial cytolethal distending toxins (CDTs) induce DNA damage response.
  • This response involves RhoA activation and p38 MAPK phosphorylation, promoting cell survival.
  • Effectors of this CDT-induced survival pathway were previously unidentified.

Purpose of the Study:

  • To identify genes mediating cell survival following CDT intoxication.
  • To elucidate the molecular mechanisms linking DNA damage and cytoskeleton dynamics.

Main Methods:

  • Screened 4492 Saccharomyces cerevisiae mutants for hypersensitivity to CdtB.
  • Utilized bioinformatics to analyze enriched signaling pathways.
  • Validated candidate genes (FEN1, TSG101) in human cells.

Main Results:

  • Identified 78 genes conferring hypersensitivity to CDT; DNA repair and endocytosis pathways were overrepresented.
  • FEN1, a DNA repair gene, was identified as a key mediator.
  • FEN1 regulates cell survival, p38 MAPK phosphorylation, RhoA activation, and actin cytoskeleton reorganization.

Conclusions:

  • A novel crosstalk exists between DNA damage response and cytoskeleton dynamics in regulating cell survival.
  • FEN1 plays a critical role in mediating CDT-induced cell survival.
  • Findings may offer insights into bacterial infection-associated carcinogenesis.

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