Escherichia coli Induces DNA Double-Strand Breaks in Eukaryotic Cells

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.

[1]  J. Galán,et al.  A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein. , 2000, Science.

[2]  F. Nowrouzian,et al.  Escherichia coli strains belonging to phylogenetic group B2 have superior capacity to persist in the intestinal microflora of infants. , 2005, The Journal of infectious diseases.

[3]  C. Fiorentini,et al.  Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Stolte,et al.  Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine , 2004, Gut.

[5]  H A Malchow,et al.  Crohn's disease and Escherichia coli. A new approach in therapy to maintain remission of colonic Crohn's disease? , 1997, Journal of clinical gastroenterology.

[6]  B. Finlay,et al.  Exploitation of mammalian host cell functions by bacterial pathogens. , 1997, Science.

[7]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[8]  M. Kuskowski,et al.  Phylogenetic distribution of virulence-associated genes among Escherichia coli isolates associated with neonatal bacterial meningitis in the Netherlands. , 2002, The Journal of infectious diseases.

[9]  I. Paulsen,et al.  The multidrug efflux protein NorM is a prototype of a new family of transporters , 1999, Molecular microbiology.

[10]  J. Stubbe,et al.  Bleomycins: towards better therapeutics , 2005, Nature Reviews Cancer.

[11]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[12]  G. Gottschalk,et al.  Analysis of the Genome Structure of the Nonpathogenic Probiotic Escherichia coli Strain Nissle 1917 , 2004, Journal of bacteriology.

[13]  B. Shen,et al.  Hybrid peptide-polyketide natural products: biosynthesis and prospects toward engineering novel molecules. , 2001, Metabolic engineering.

[14]  X. Tu,et al.  Enteropathogenic and enterohaemorrhagic Escherichia coli deliver a novel effector called Cif, which blocks cell cycle G2/M transition , 2003, Molecular microbiology.

[15]  J. Sarkaria,et al.  Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. , 1999, Cancer research.

[16]  Christopher T Walsh,et al.  Polyketide and Nonribosomal Peptide Antibiotics: Modularity and Versatility , 2004, Science.

[17]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[18]  S. Falkow,et al.  Haemolysin contributes to virulence of extra-intestinal E. coli infections , 1981, Nature.

[19]  B. Rembacken,et al.  Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial , 1999, The Lancet.

[20]  A. Sancar,et al.  Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. , 2004, Annual review of biochemistry.

[21]  Ulrich Dobrindt,et al.  Prokaryotic Chromosomes and Disease , 2003, Science.

[22]  F. Blattner,et al.  Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Lax Bacterial toxins and cancer — a case to answer? , 2005, Nature Reviews Microbiology.

[24]  F. Taieb,et al.  Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle. , 2005, Trends in microbiology.

[25]  Jacques Elion,et al.  The Link between Phylogeny and Virulence inEscherichia coli Extraintestinal Infection , 1999, Infection and Immunity.

[26]  Kira J. Weissman,et al.  Combinatorial biosynthesis of reduced polyketides , 2005, Nature Reviews Microbiology.

[27]  Harry L. T. Mobley,et al.  Pathogenic Escherichia coli , 2004, Nature Reviews Microbiology.

[28]  C. Hutchinson Polyketide and non-ribosomal peptide synthases: Falling together by coming apart , 2003, Proceedings of the National Academy of Sciences of the United States of America.