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Cytolethal distending toxins and activation of DNA damage-dependent checkpoint responses
Teresa Frisan1, Ximena Cortes-Bratti, Monica Thelestam
1Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden. teresa.frisan@mtc.ki.se
Abstract:
Cytolethal distending toxins (CDTs) are unique among bacterial protein toxins in their ability to cause DNA damage, due to their functional similarity to the mammalian deoxyribonuclease I (DNase I). The cellular response to CDT intoxication is characterised by activation of DNA damage-induced checkpoint responses, and the final outcome is cell type dependent. Cells of epithelial origin and normal keratinocytes are arrested in the G2 phase of the cell cycle, normal fibroblasts are also arrested in G1, while B cells die of apoptosis. CDTs are encoded by three linked genes (cdtA, cdtB and cdtC), and CdtB is the toxin subunit which possesses the DNase I-like activity. All the three genes have to be present in the bacterium in order to produce an active cytotoxin, however cytotoxic Haemophilus ducreyi CDT, purified from a CdtABC recombinant E. coli strain, contains the CdtB and CdtC subunits, suggesting that they constitute the holotoxin and that CdtC may be required for CdtB internalization. The role of the CdtA subunit is currently unknown, but it might modify and therefore activate CdtC. This review will focus on the cellular responses induced by CDTs in mammalian cells.
Insights
Cytolethal distending toxins (CDTs) damage bacterial DNA, similar to DNase I. Cellular responses to CDT intoxication vary by cell type, leading to cell cycle arrest or apoptosis.
Area of Science:
- Microbiology
- Cell Biology
- Toxicology
Background:
- Cytolethal distending toxins (CDTs) are bacterial protein toxins.
- CDTs induce DNA damage, mimicking mammalian deoxyribonuclease I (DNase I).
- Cellular responses to CDTs involve DNA damage checkpoints and are cell-type specific.
Purpose of the Study:
- To review the cellular responses induced by CDTs in mammalian cells.
- To elucidate the mechanism of CDT-induced DNA damage and cell cycle effects.
- To discuss the roles of CDT subunits (CdtA, CdtB, CdtC) in toxin activity.
Main Methods:
- Literature review of studies on CDTs and their effects on mammalian cells.
- Analysis of the genetic basis of CDT production (cdtA, cdtB, cdtC genes).
- Examination of the enzymatic activity of the CdtB subunit and its DNase I-like function.
Main Results:
- CDT intoxication activates DNA damage checkpoints.
- Cellular outcomes include G2/G1 cell cycle arrest (epithelial cells, keratinocytes, fibroblasts) or apoptosis (B cells).
- The CdtB subunit possesses DNase I-like activity, while CdtC may facilitate CdtB internalization.
Conclusions:
- CDTs are potent genotoxins with diverse effects on mammalian cell cycles.
- The CdtABC complex is required for full CDT activity, with CdtB being the active subunit.
- Further research is needed to clarify the role of CdtA in CDT function.