Cross-linking gut bacteria to cancer – Microbiology Research

Certain strains of Escherichia coli produce the natural product colibactin, which is a chemically unstable genotoxin, and increasing evidence suggests that colibactin is associated with colorectal carcinogenesis. Previous work indicted that colibactin contains two cyclopropane moieties that form DNA interstrand cross-links (ICLs). However, characterization of the structure of colibactin and its genotoxic mechanism has been challenging. In this study, Carlson, Haslecker et al. report that colibactin specifically binds in adenine- and thymine (AT)-rich regions in the minor groove. Moreover, they report that colibactin induces ICLs between two adenines on opposing strands within a specific sequence motif. Importantly, the preference for AT-rich sequences is consistent with the locations of mutational signatures induced by colibactin that have previously been detected in the genomes of colorectal cancer cells. The authors went on to elucidate the structure of the colibactin–DNA ICL and discovered that a chemically unstable positively charged central α-ketoiminium of colibactin mediates the sequence specificity of DNA cross-linking. In sum, the findings of this study have greatly advanced our understanding of the structure and genotoxic activity of colibactin and its role in colorectal carcinogenesis.