Journal
SCIENCE
Volume 363, Issue 6428, Pages 709-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aar7785
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Funding
- Packard Fellowship for Science and Engineering
- Damon Runyon-Rachleff Innovation Award
- National Institutes of Health [R01 CA208834, R01 CA154426, R01 ES022872]
- National Institute of Environmental Health Sciences [R44 ES024698]
- Center for Environmental Health Sciences [P30 ES002109]
- National Cancer Institute [R50-CA211256]
- U.S. National Institutes of Health
- National Cancer Institute (Cancer Center Support Grant) [CA-77598]
- American Cancer Society-New England Division Postdoctoral Fellowship [PF-16-122-01-CDD]
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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.
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