{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:38:23Z","timestamp":1790797103159,"version":"4.1.0"},"reference-count":58,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T00:00:00Z","timestamp":1521504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,5,2]],"date-time":"2018-05-02T00:00:00Z","timestamp":1525219200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-13-BSV1-0028-01"],"award-info":[{"award-number":["ANR-13-BSV1-0028-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["PLBIO13-123"],"award-info":[{"award-number":["PLBIO13-123"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2018,5,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Colibactins are hybrid polyketide-nonribosomal peptides produced by\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    ,\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    , and other\n                    <jats:italic>Enterobacteriaceae<\/jats:italic>\n                    harboring the\n                    <jats:italic>pks<\/jats:italic>\n                    genomic island. These genotoxic metabolites are produced by\n                    <jats:italic>pks<\/jats:italic>\n                    -encoded peptide-polyketide synthases as inactive prodrugs called precolibactins, which are then converted to colibactins by deacylation for DNA-damaging effects. Colibactins are bona fide virulence factors and are suspected of promoting colorectal carcinogenesis when produced by intestinal\n                    <jats:italic>E.\u00a0coli<\/jats:italic>\n                    . Natural active colibactins have not been isolated, and how they induce DNA damage in the eukaryotic host cell is poorly characterized. Here, we show that DNA strands are cross-linked covalently when exposed to enterobacteria producing colibactins. DNA cross-linking is abrogated in a\n                    <jats:italic>clbP<\/jats:italic>\n                    mutant unable to deacetylate precolibactins or by adding the colibactin self-resistance protein ClbS, confirming the involvement of the mature forms of colibactins. A similar DNA-damaging mechanism is observed\n                    <jats:italic>in cellulo<\/jats:italic>\n                    , where interstrand cross-links are detected in the genomic DNA of cultured human cells exposed to colibactin-producing bacteria. The intoxicated cells exhibit replication stress, activation of ataxia-telangiectasia and Rad3-related kinase (ATR), and recruitment of the DNA cross-link repair Fanconi anemia protein D2 (FANCD2) protein. In contrast, inhibition of ATR or knockdown of FANCD2 reduces the survival of cells exposed to colibactin-producing bacteria. These findings demonstrate that DNA interstrand cross-linking is the critical mechanism of colibactin-induced DNA damage in infected cells.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Colorectal cancer is the third-most-common cause of cancer death. In addition to known risk factors such as high-fat diets and alcohol consumption, genotoxic intestinal\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    bacteria producing colibactin are proposed to play a role in colon cancer development. Here, by using transient infections with genotoxic\n                    <jats:italic>E.\u00a0coli<\/jats:italic>\n                    , we showed that colibactins directly generate DNA cross-links\n                    <jats:italic>in cellulo<\/jats:italic>\n                    . Such lesions are converted into double-strand breaks during the repair response. DNA cross-links, akin to those induced by metabolites of alcohol and high-fat diets and by widely used anticancer drugs, are both severely mutagenic and profoundly cytotoxic lesions. This finding of a direct induction of DNA cross-links by a bacterium should facilitate delineating the role of\n                    <jats:italic>E.\u00a0coli<\/jats:italic>\n                    in colon cancer and engineering new anticancer agents.\n                  <\/jats:p>","DOI":"10.1128\/mbio.02393-17","type":"journal-article","created":{"date-parts":[[2018,3,19]],"date-time":"2018-03-19T06:00:36Z","timestamp":1521439236000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":243,"title":["The Colibactin Genotoxin Generates DNA Interstrand Cross-Links in Infected Cells"],"prefix":"10.1128","volume":"9","author":[{"given":"Nad\u00e8ge","family":"Bossuet-Greif","sequence":"first","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Oswald","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Nougayr\u00e8de","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, 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