Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage

Li, Z.-R.; Li, J.; Cai, W.; Lai, J.; McKinnie, S.; Zhang, W.-P.; Moore, B.; Zhang, W.; Qian, P.-Y.

doi:10.1101/530204

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bioRxiv · 10.1101/530204

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage

Li, Z.-R.·Li, J.·Cai, W.·Lai, J.·McKinnie, S.·Zhang, W.-P.·Moore, B.·Zhang, W.·Qian, P.-Y.

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Abstract

Colibactin is an as-yet-uncharacterized human gut bacterial genotoxin, whose biosynthesis is linked to clb genomic island that distributes widespread in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumor formation and enhance progression of colorectal cancer (CRC) via DNA double-strand breaks (DSBs)-induced cellular senescence and death; however, the chemical basis contributing to the pathogenesis at the molecular level remains elusive. Here we report the discovery and the mechanism of action of colibactin-645 as the highly sought final colibactin metabolite with a novel molecular scaffold. Colibactin-645 recapitulates its previously assumed genotoxicity and cytotoxicity, exhibiting a strong DNA DSBs activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also present a complete model for colibactin biosynthesis, revealing an unprecedented dual function of the aminomalonate-utilizing polyketide synthases. This work thus provides the first molecular basis for colibactins genotoxic activity and facilitates further mechanistic study of colibactin-related CRC incidence and prevention.

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Li, Z.-R., Li, J., Cai, W., Lai, J., McKinnie, S., Zhang, W.-P., Moore, B., Zhang, W., Qian, P.-Y.. 2019-01-24. Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage. https://doi.org/10.1101/530204

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