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Colibactin DNA damage signature indicates causative role in colorectal cancer

By Paulina J. DziubaƄska-Kusibab, Hilmar Berger, Federica Battistini, Britta A. M. Bouwman, Amina Iftekhar, Riku Katainen, Nicola Crosetto, Modesto Orozco, Lauri A. Aaltonen, Thomas F. Meyer

Posted 25 Oct 2019
bioRxiv DOI: 10.1101/819854

Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs) in human cells. We investigated if colibactin creates a particular DNA damage signature in infected cells by identifying DSBs in colon cells after infection with pks+ E.coli. Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameric sequence motifs, exhibiting a particularly narrow minor groove width and extremely negative electrostatic potential. This corresponded with the binding characteristics of colibactin to double-stranded DNA, as elucidated by docking and molecular dynamics simulations. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the identified motifs in colorectal cancers. Our work provides direct evidence for a role of colibactin in the etiology of human cancer.

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