The human gut bacterial genotoxin colibactin alkylates DNA
Name
nihms-1014865.pdf
Description
Accepted version
Size
762.78 KB
Format
Adobe PDF
Checksum (MD5)
cdffd5cd0355870bbf9eb8627ea8380d
Author(s)
Ngo, Lizzie
Samson, Leona D.
Engelward, Bevin P.
Date Issued
February 14, 2019
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Wilson, Matthew R. et al. “The human gut bacterial genotoxin colibactin alkylates DNA.” Science 363 (2019): 6428 © 2019 The Author(s)
Version
Author's final manuscript
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.
Subjects
Multidisciplinary
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/science.aar7785
