The human gut bacterial genotoxin colibactin alkylates DNA
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- 15 February 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 363 (6428), 709-+
- https://doi.org/10.1126/science.aar7785
Abstract
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.Keywords
Funding Information
- David and Lucile Packard Foundation (2013-39267)
- American Cancer Society (PF-16-122-01-CDD)
- National Cancer Institute (5R01CA208834-02)
- National Cancer Institute (R50-CA211256)
- National Cancer Institute (CA-77598)
- Damon Runyon Cancer Research Foundation (27-14)
- National Institute of Environmental Health Sciences (R01 ES022872)
- Damon Runyon Cancer Research Foundation (DRG-2205-14)
- National Institute of Environmental Health Sciences (R44 ES024698)
- National Institute of Environmental Health Sciences (P30 ES002109)
- National Cancer Institute (R01 CA154426)
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