The human gut bacterial genotoxin colibactin alkylates DNA
Author(s)Ngo, Lizzie; Samson, Leona D.; Engelward, Bevin P.
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Certain Escherichia coli strains residing in the human gut produce colibactin, a small-molecule genotoxin implicated in colorectal cancer pathogenesis. However, colibactin’s chemical structure and the molecular mechanism underlying its genotoxic effects have remained unknown for more than a decade. Here we combine an untargeted DNA adductomics approach with chemical synthesis to identify and characterize a covalent DNA modification from human cell lines treated with colibactin-producing E. coli. Our data establish that colibactin alkylates DNA with an unusual electrophilic cyclopropane. We show that this metabolite is formed in mice colonized by colibactin-producing E. coli and is likely derived from an initially formed, unstable colibactin-DNA adduct. Our findings reveal a potential biomarker for colibactin exposure and provide mechanistic insights into how a gut microbe may contribute to colorectal carcinogenesis.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering
American Association for the Advancement of Science (AAAS)
Wilson, Matthew R. et al. “The human gut bacterial genotoxin colibactin alkylates DNA.” Science 363 (2019): 6428 © 2019 The Author(s)
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