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

Lina Guerra, Riccardo Guidi, Ilse Slot, Simone Callegari, Ramakrishna Sompallae, Carol L. Pickett, Stefan Åström, Frederik Eisele, Dieter Wolf, Camilla Sjögren, Maria G. Masucci, Teresa Frisan

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2735-2742
Number of pages8
JournalJournal of Cell Science
Volume124
Issue number16
DOIs
StatePublished - Aug 15 2011

Keywords

  • Actin cytoskeleton
  • Cell survival
  • Cytolethal distending toxin
  • DNA damage
  • FEN1
  • RhoA
  • TSG101

ASJC Scopus subject areas

  • Cell Biology

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