Colibactin DNA damage signature indicates mutational impact in colorectal cancer

Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs). We investigated if colibactin creates a particular DNA damage signature in infected human cells. Genomic contexts of colibactin-induced DSBs were enriched for a distinct AT-rich hexameric sequence motif. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the motif in colorectal cancers. Moreover, the exact break point location corresponded with mutational hot spots in these cancers corresponding to a distinct trinucleotide signature. This work provides evidence for a role of colibactin in the etiology of human cancer. Genome-wide and unbiased profiling of DNA double-strand breaks upon colibactin-positive (pks+) and colibactin-negative (pks-) E.coli infection, as well as upon etoposide treatment and no-treatment using Breaks Labeling in Situ and Sequencing (BLISS)