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Science. 2019 Feb 15;363(6428). pii: eaar7785. doi: 10.1126/science.aar7785.

The human gut bacterial genotoxin colibactin alkylates DNA.

Author information

1
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
2
Masonic Cancer Center, University of Minnesota, 2231 Sixth Street Southeast, Minneapolis, MN 55455, USA.
3
Department of Immunology and Infectious Diseases and Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
4
Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
5
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
6
Department of Medical Oncology, Dana-Farber Institute, Boston, MA 02115, USA.
7
Masonic Cancer Center, University of Minnesota, 2231 Sixth Street Southeast, Minneapolis, MN 55455, USA. balskus@chemistry.harvard.edu balbo006@umn.edu.
8
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA. balskus@chemistry.harvard.edu balbo006@umn.edu.
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Contributed equally

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.

Comment in

PMID:
30765538
PMCID:
PMC6407708
DOI:
10.1126/science.aar7785
[Indexed for MEDLINE]
Free PMC Article

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