Colibactin DNA damage signature indicates causative role in colorectal cancer

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.