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

J Cell Sci. 2011 Aug 15;124(Pt 16):2735-42. doi: 10.1242/jcs.085845.


The DNA damage response triggered by bacterial cytolethal distending toxins (CDTs) is associated with activation of the actin-regulating protein RhoA and phosphorylation of the downstream-regulated mitogen-activated protein kinase (MAPK) p38, which promotes the survival of intoxicated (i.e. cells exposed to a bacterial toxin) cells. To identify the effectors of this CDT-induced survival response, we screened a library of 4492 Saccharomyces cerevisiae mutants that carry deletions in nonessential genes for reduced growth following inducible expression of CdtB. We identified 78 genes whose deletion confers hypersensitivity to toxin. Bioinformatics analysis revealed that DNA repair and endocytosis were the two most overrepresented signaling pathways. Among the human orthologs present in our data set, FEN1 and TSG101 regulate DNA repair and endocytosis, respectively, and also share common interacting partners with RhoA. We further demonstrate that FEN1, but not TSG101, regulates cell survival, MAPK p38 phosphorylation, RhoA activation and actin cytoskeleton reorganization in response to DNA damage. Our data reveal a previously unrecognized crosstalk between DNA damage and cytoskeleton dynamics in the regulation of cell survival, and might provide new insights on the role of chronic bacteria infection in carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • Cell Survival* / genetics
  • Computational Biology
  • Cytoskeleton / metabolism*
  • Cytoskeleton / ultrastructure
  • DNA Damage
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endocytosis / genetics
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Flap Endonucleases / genetics
  • Flap Endonucleases / metabolism*
  • HeLa Cells
  • Humans
  • Saccharomyces cerevisiae / genetics
  • Sequence Deletion / genetics
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transgenes / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism*


  • Actins
  • Bacterial Toxins
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Transcription Factors
  • Tsg101 protein
  • cytolethal distending toxin
  • RHOA protein, human
  • p38 Mitogen-Activated Protein Kinases
  • Flap Endonucleases
  • rhoA GTP-Binding Protein