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 journalArticle

14 Citations (Scopus)

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

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Mutagens
DNA
Escherichia coli
DNA Adducts
colibactin
Molecular Structure
Colorectal Neoplasms
Carcinogenesis
Biomarkers
Cell Line

PubMed: MeSH publication types

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

Cite this

Wilson, M. R., Jiang, Y., Villalta, P. W., Stornetta, A., Boudreau, P. D., Carrá, A., ... Balskus, E. P. (2019). The human gut bacterial genotoxin colibactin alkylates DNA. Science, 363(6428), [eaar7785]. https://doi.org/10.1126/science.aar7785

The human gut bacterial genotoxin colibactin alkylates DNA. / Wilson, Matthew R.; Jiang, Yindi; Villalta, Peter W.; Stornetta, Alessia; Boudreau, Paul D.; Carrá, Andrea; Brennan, Caitlin A.; Chun, Eunyoung; Ngo, Lizzie; Samson, Leona D.; Engelward, Bevin P.; Garrett, Wendy S.; Balbo, Silvia; Balskus, Emily P.

In: Science, Vol. 363, No. 6428, eaar7785, 15.02.2019.

Research output: Contribution to journalArticle

Wilson, MR, Jiang, Y, Villalta, PW, Stornetta, A, Boudreau, PD, Carrá, A, Brennan, CA, Chun, E, Ngo, L, Samson, LD, Engelward, BP, Garrett, WS, Balbo, S & Balskus, EP 2019, 'The human gut bacterial genotoxin colibactin alkylates DNA', Science, vol. 363, no. 6428, eaar7785. https://doi.org/10.1126/science.aar7785
Wilson, Matthew R. ; Jiang, Yindi ; Villalta, Peter W. ; Stornetta, Alessia ; Boudreau, Paul D. ; Carrá, Andrea ; Brennan, Caitlin A. ; Chun, Eunyoung ; Ngo, Lizzie ; Samson, Leona D. ; Engelward, Bevin P. ; Garrett, Wendy S. ; Balbo, Silvia ; Balskus, Emily P. / The human gut bacterial genotoxin colibactin alkylates DNA. In: Science. 2019 ; Vol. 363, No. 6428.
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