The human gut bacterial genotoxin colibactin alkylates DNA

Matthew R. Wilson, Yindi Jiang, Peter W. Villalta, Alessia Stornetta, Paul D. Boudreau, Andrea Carrá, Caitlin A. Brennan, Eunyoung Chun, Lizzie Ngo, Leona D. Samson, Bevin P. Engelward, Wendy S. Garrett, Silvia Balbo, Emily P. Balskus

Research output: Contribution to journalArticlepeer-review

329 Scopus citations

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.

Original languageEnglish (US)
Article numbereaar7785
JournalScience
Volume363
Issue number6428
DOIs
StatePublished - Feb 15 2019

Bibliographical note

Publisher Copyright:
© The Authors, some rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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