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Photoactivated Colibactin Probes Induce Cellular DNA Damage
Lindon W K Moodie1, Madlen Hubert2, Xin Zhou3
1Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
Angewandte Chemie (International Ed. in English)
|December 4, 2018
Summary
Colibactin, a genotoxic molecule from gut bacteria, directly damages DNA. Researchers used photolabile probes to show its "warhead" and prodrug strategy contribute to DNA alkylation and cancer progression.
Area of Science:
- Microbiology
- Genotoxicity
- Molecular Biology
Background:
- Colibactin is a genotoxic small molecule produced by pks-positive bacteria in the human gut microbiota.
- Pks-positive bacteria are associated with colorectal cancer progression.
- Colibactin is synthesized as a prodrug and activated by the producing bacteria.
Purpose of the Study:
- To investigate the role of colibactin's electrophilic cyclopropane motif (the putative
Main Methods:
- Synthesis of photolabile colibactin probes.
- Irradiation of probes in HeLa cells to induce a genotoxic phenotype.
- DNA cross-linking and imaging studies using clickable colibactin analogues.
Main Results:
- Photolabile probes mimicked the genotoxic effects of pks-positive bacteria upon irradiation.
- DNA cross-linking and imaging studies supported direct DNA alkylation by colibactin.
Conclusions:
- The electrophilic cyclopropane motif is crucial for colibactin's genotoxicity.
- Colibactin directly targets and alkylates DNA, contributing to its genotoxic effects and potential role in colorectal cancer.
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