Cited by 635Synthesis and pharmacology of benzodiazepine derivativesEscherichia coli research studiesBacterial Genetics and Biotechnology

The Human Gut Bacterial Genotoxin Colibactin Alkylates DNA

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Wilson, Matthew R., Jiang, Yindi, Villalta, Peter W., Stornetta, Alessia, Boudreau, Paul D., Carrá, Andrea, Brennan, Caitlin A., Chun, Eunyoung +6 more·2019·Science

Abstract

Bacterial warhead targets DNA: The bacterial toxin colibactin causes double-stranded DNA breaks and is associated with the occurrence of bacterially induced colorectal cancer in humans. However, isolation of colibactin is difficult, and its mode of action is poorly understood. Wilson et al. studied Escherichia coli that contain the biosynthetic gene island called pks , which is associated with colibactin production (see the Perspective by Bleich and Arthur). They identified the DNA adducts that resulted from incubating pks + E. coli in human cells. To overcome the lack of colibactin for direct analysis, mimics of the pks product were synthesized. From the resulting synthetic adenine-colibactin adducts, it became evident that alkylation via a cyclopropane “warhead” breaks the DNA strands. Similar DNA adducts were then identified in the gut epithelia of mice infected with pks + E. coli. Science , this issue p. eaar7785 ; see also p. 689

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  • Metabolites produced by some intestinal microbiota may be genotoxic and can directly induce DNA damage of host cells or modulate host cell signaling pathways involved in cell proliferation and apoptosis.

    “Metabolites produced by some intestinal microbiota may be genotoxic and can directly induce DNA damage of host cells or modulate the basic host cell signaling pathways involved in cell proliferation and apoptosis.”
  • Strong experimental evidence indicates that additional microbes initiate cancer through genotoxin-mediated mutagenesis; specifically, colibactin, cytolethal distending toxin, and Bacteroides fragilis toxin produce mutational signatures found in colorectal, head and neck, and urinary tract cancers.

    “Strong experimental evidence suggests that additional microbes initiate cancer through genotoxin-mediated mutagenesis; in particular, colibactin (a DNA alkylator), cytolethal distending toxin (CDT; direct DNAse activity), and Bacteroides fragilis toxin (Bft; ROS producer) cause mutational signatures found in colorectal, head and neck, and urinary tract cancers (22, 37–41).”

    From The microbiome and human cancer (2021) · cites this paper as [37]

  • Intratumor microbes have cancer-specific effects on gastrointestinal and urinary tract mutagenesis via secreted genotoxins, most notably pks+ E. coli-derived colibactin and B. fragilis-derived toxin.

    “intratumor microbes have been reported to have cancer-specific effects on (i) gastrointestinal and urinary tract mutagenesis via secreted genotoxins, most notably pks+ E. coli-derived colibactin and B. fragilis-derived toxin (22, 37, 38, 40, 41)”

    From The microbiome and human cancer (2021) · cites this paper as [37]

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Authors
Wilson, M. R., Jiang, Y., Villalta, P. W., Stornetta, A., Boudreau, P. D., Carrá, A., Brennan, C. A., Chun, E., Ngo, L., Samson, L. D., Engelward, B. P., Garrett, W. S., Balbo, S., & Balskus, E. P.
Affiliations
  • Harvard University (US)
  • University of Minnesota (US)
  • Masonic Cancer Center, University of Minnesota, 2231 Sixth Street Southeast, Minneapolis, MN 55455, USA.
  • Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
  • Massachusetts Institute of Technology (US)
  • Broad Institute (US)
Corresponding author
  • Wilson, Matthew R.
  • Jiang, Yindi
  • Balbo, Silvia
  • Balskus, Emily P.
Venue
Science
Published
2019-02-15
Volume
363
Issue
6428
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2912413992
Cited by
635
References
41
Citations by year
2026: 71 · 2025: 93 · 2024: 94 · 2023: 76 · 2022: 85 · 2021: 101 · 2020: 70 · 2019: 44
FWCI
29.40
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • David and Lucile Packard Foundation (2013-39267)
  • American Cancer Society (PF-16-122-01-CDD)
  • National Cancer Institute (5R01CA208834-02, R50-CA211256, CA-77598, R01 CA154426)
  • Damon Runyon Cancer Research Foundation (27-14, DRG-2205-14)
  • National Institute of Environmental Health Sciences (R01 ES022872, R44 ES024698, P30 ES002109)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and pharmacology of benzodiazepine derivatives
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
colibactin, DNA alkylation, DNA adducts, Escherichia coli, DNA double-strand breaks, colorectal cancer, intestinal epithelium, bacterial genotoxins
MeSH terms
Gastrointestinal Microbiome, Alkylating Agents, Alkylation, Animals, Cyclopropanes, DNA Damage, Escherichia coli, Germ-Free Life, HeLa Cells, Humans, Mice, Inbred C57BL, Mutagens, Peptides, Colorectal Neoplasms, DNA Adducts, HT29 Cells, Mice, Polyketides, Carcinogenesis

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