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

TitleMacrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage
Publication TypeJournal Article
Year of Publication2019
AuthorsLi Z.R, Li J., Cai W.L, Lai J.YH, McKinnie S.MK, Zhang W.P, Moore BS, Zhang W.J, Qian PY
Date Published2019/10
Type of ArticleArticle
ISBN Number1755-4330
Accession NumberWOS:000487584400008
Keywordsactivation; biosynthesis; bleomycin; chemistry; Damage; health; human microbiome; in-vivo; insights; mechanism; repair

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA doublestrand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase CIbO and the amidase CIbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention.

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