title: Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival.
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.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Box 285, S-171 77 Stockholm, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Guerra
authors.forename: Riccardo
authors.initials: R
authors.lastname: Guidi
authors.forename: Ilse
authors.initials: I
authors.lastname: Slot
authors.forename: Simone
authors.initials: S
authors.lastname: Callegari
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sompallae
authors.forename: Carol L
authors.initials: CL
authors.lastname: Pickett
authors.forename: Stefan
authors.initials: S
authors.lastname: Åström
authors.forename: Frederik
authors.initials: F
authors.lastname: Eisele
authors.forename: Dieter
authors.initials: D
authors.lastname: Wolf
authors.forename: Camilla
authors.initials: C
authors.lastname: Sjögren
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
authors.forename: Teresa
authors.initials: T
authors.lastname: Frisan
mesh_terms: D000199:Actins / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D019295:Computational Biology; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000099177:Tsg101 Protein
chemical_list: D000199:Actins; D001427:Bacterial Toxins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D045585:Flap Endonucleases; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D000099177:Tsg101 Protein; C067044:cytolethal distending toxin; C066737:RHOA protein, human