TY - JOUR
T1 - Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival
AU - Guerra, Lina
AU - Guidi, Riccardo
AU - Slot, Ilse
AU - Callegari, Simone
AU - Sompallae, Ramakrishna
AU - Pickett, Carol L.
AU - Åström, Stefan
AU - Eisele, Frederik
AU - Wolf, Dieter
AU - Sjögren, Camilla
AU - Masucci, Maria G.
AU - Frisan, Teresa
PY - 2011/8/15
Y1 - 2011/8/15
N2 - 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.
AB - 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.
KW - Actin cytoskeleton
KW - Cell survival
KW - Cytolethal distending toxin
KW - DNA damage
KW - FEN1
KW - RhoA
KW - TSG101
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UR - http://www.scopus.com/inward/citedby.url?scp=79961160914&partnerID=8YFLogxK
U2 - 10.1242/jcs.085845
DO - 10.1242/jcs.085845
M3 - Article
C2 - 21807938
AN - SCOPUS:79961160914
SN - 0021-9533
VL - 124
SP - 2735
EP - 2742
JO - Journal of Cell Science
JF - Journal of Cell Science
IS - 16
ER -