Escherichia coli Induces DNA Double-Strand Breaks in Eukaryotic Cells

Abstract

Transient infection of eukaryotic cells with commensal and extraintestinal pathogenic Escherichia coli of phylogenetic group B2 blocks mitosis and induces megalocytosis. This trait is linked to a widely spread genomic island that encodes giant modular nonribosomal peptide and polyketide synthases. Contact with E. coli expressing this gene cluster causes DNA double-strand breaks and activation of the DNA damage checkpoint pathway, leading to cell cycle arrest and eventually to cell death. Discovery of hybrid peptide-polyketide genotoxins in E. coli will change our view on pathogenesis and commensalism and open new biotechnological applications.

Listeria monocytogenesinduces host DNA damage and delays the host cell cycle to promote infection

“…Producers of genotoxins, such as cytolethal distending toxins or colibactin, cause direct DNA injury, inducing genomic instability and ultimately cell cycle arrest and cell death. 7,[35][36][37] Other bacteria, such as C. trachomatis, 19 Pseudomonas aeruginosa, 38 H. pylori, 12 N. gonorrhoeae 39 , and Shigella flexneri, 40 induce the production of reactive oxygen species (ROS) that promote oxidative DNA damage, thereby increasing γH2A.X levels and impairing host DNA repair mechanisms. To our knowledge, Lm does not express toxins that can directly injure host DNA.…”

“…Bacterial effectors such as cyclomodulins 4,5 can inhibit or stimulate the eukaryotic cell cycle, playing roles in disease. While Shigella and pathogenic Escherichia coli block host cells in the G 2 /M phase transition, [6][7][8] Neisseria gonorrhoeae and Porphyromonas gingivalis inhibit cell proliferation via G 1 arrest. 9,10 Conversely, Helicobacter pylori enhances gastric epithelial cell proliferation by stimulating cell cycle progression.…”

When our genome is targeted by pathogenic bacteria

“…The bacteria-host association typically provides reciprocal benefits; nonetheless, some pathogenic strains of E. coli have deleterious effects in the intestine. The pathogenicity of E. coli belonging to B2 phylogenic group is associated with the presence of a genomic island called pks, which harbors approximately 20 open reading frames involved in the biosynthesis of the genotoxin colibactin [3]. This molecule is a hybrid nonribosomal polypeptide-polyketide compound resulting from the enzymatic activities encoded by the pks gene cluster.…”

“…The in vitro infection of eukaryotic cells with E. coli carrying a pks island results in DSBs which trigger the activation of ATM kinase and downstream signaling pathways and effectors, such as Chk2 and Chk1 [3] (Fig. 1a).…”

“…From a historical point of view, Helicobacter pylori has been tremendously useful to unravel the mysteries in this domain [2]. In 2006, the discovery of the Escherichia coli genotoxin colibactin, which induces DNA double-strand breaks (DSBs), led to a major breakthrough in the field [3]. Within a few years, the genotoxicity of many bacteria has been described.…”