Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1225, F-31076 Toulouse, France.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11537-42. doi: 10.1073/pnas.1001261107. Epub 2010 Jun 7.
Escherichia coli is a normal inhabitant of the human gut. However, E. coli strains of phylogenetic group B2 harbor a genomic island called "pks" that codes for the production of a polyketide-peptide genotoxin, Colibactin. Here we report that in vivo infection with E. coli harboring the pks island, but not with a pks isogenic mutant, induced the formation of phosphorylated H2AX foci in mouse enterocytes. We show that a single, short exposure of cultured mammalian epithelial cells to live pks(+) E. coli at low infectious doses induced a transient DNA damage response followed by cell division with signs of incomplete DNA repair, leading to anaphase bridges and chromosome aberrations. Micronuclei, aneuploidy, ring chromosomes, and anaphase bridges persisted in dividing cells up to 21 d after infection, indicating occurrence of breakage-fusion-bridge cycles and chromosomal instability. Exposed cells exhibited a significant increase in gene mutation frequency and anchorage-independent colony formation, demonstrating the infection mutagenic and transforming potential. Therefore, colon colonization with these E. coli strains harboring the pks island could contribute to the development of sporadic colorectal cancer.
大肠杆菌是人类肠道的正常寄居者。然而，具有进化群 B2 的大肠杆菌菌株携带有一个被称为“pks”的基因组岛，该岛编码产生一种多酮肽遗传毒素，即 Colibactin。在这里，我们报告说，体内感染携带 pks 岛的大肠杆菌，但不感染具有 pks 同基因突变的大肠杆菌，会在小鼠肠细胞中诱导形成磷酸化 H2AX 焦点。我们表明，在低感染剂量下，培养的哺乳动物上皮细胞单次短暂暴露于活的 pks(+)大肠杆菌，会引发短暂的 DNA 损伤反应，随后进行有丝分裂，并伴有不完全的 DNA 修复迹象，导致后期桥和染色体异常。在感染后 21 天内，有丝分裂细胞中仍然存在微核、非整倍体、环状染色体和后期桥，表明发生了断裂-融合-桥循环和染色体不稳定性。暴露的细胞显示出基因突变速率和非锚定独立集落形成的显著增加，证明了感染的诱变和转化潜力。因此，这些携带 pks 岛的大肠杆菌菌株的结肠定植可能有助于散发性结直肠癌的发展。
