Bacterial genotoxins: The long journey to the nucleus of mammalian cells

Abstract

Bacterial protein genotoxins target the DNA of eukaryotic cells, causing DNA single and double strand breaks. The final outcome of the intoxication is induction of DNA damage responses and activation of DNA repair pathways. When the damage is beyond repair, the target cell either undergoes apoptosis or enters a permanent quiescent stage, known as cellular senescence. In certain instances, intoxicated cells can survive and proliferate. This event leads to accumulation of genomic instability and acquisition of malignant traits, underlining the carcinogenic potential of these toxins. The toxicity is dependent on the toxins' internalization and trafficking from the extracellular environment to the nucleus, and requires a complex interaction with several cellular membrane compartments: the plasma membrane, the endosomes, the trans Golgi network and the endoplasmic reticulum, and finally the nucleus. This review will discuss the current knowledge of the bacterial genotoxins internalization pathways and will highlight the issues that still remain unanswered. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.

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“…166,167 These bacterial genotoxins fall into at least two chemical families-proteins or complex multiring peptide-polyketide structures similar to many fungal antibiotics-and they induce single-or doublestrand DNA breaks (SSB or DSB) in the genomes of infected mammalian cells. 168 One subunit of the cytolethal distending toxin (CDT) heterotrimeric protein common to several extracellular pathogens displays homology to mammalian DNAse I. ggg In order to exert a genotoxic effect, the toxin molecule must first enter the host cell nucleus.…”