Colibactin is a genotoxic, natural product produced by certain members of the human gut microbiome and highly associated with colorectal cancer (CRC), the second-leading cause of cancer death. Colibactin exhibits its genotoxicity through the formation of DNA interstrand crosslinks (ICLs). It is believed that persistence of colibactin ICLs causes oncogenic single-base substitutions or indel mutations while colibactin ICL decomposition or misrepair leads to DNA double-strand breaks. While these phenotypes are well-reported, their underlying chemical details are not well understood. To help fill this gap in knowledge, we directly characterized the specificity and structure of colibactin-DNA ICLs within short oligonucleotides by multiple approaches including  gel electrophoresis, mass spectrometry, and molecular modeling. We identified several DNA sequences that undergo ICL formation by colibactin and obtained new insights regarding colibactin’s sequence specificity, crosslink length, binding stoichiometry, groove binding, and atom-connectivity with DNA. Taken together, this study provides direct, biochemical support for colibactin’s mutagenicity and genotoxicity, reveals new insights about colibactin-DNA interactions, and furthers our understanding of colibactin’s role in CRC pathogenesis.

Biochemical characterization of colibactin-DNA interstrand crosslink formation using short oligonucleotides

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.