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Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival
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2011 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 16, 2735-2742 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 124, no 16, 2735-2742 p.
Keyword [en]
Cytolethal distending toxin, DNA damage, FEN1, Cell survival, TSG101, RhoA, Actin cytoskeleton
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-68318DOI: 10.1242/jcs.085845ISI: 000293352800008OAI: oai:DiVA.org:su-68318DiVA: diva2:477390
Note
authorCount :12Available from: 2012-01-13 Created: 2012-01-03 Last updated: 2017-12-08Bibliographically approved

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Åström, Stefan
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