The human gut bacterial genotoxin colibactin alkylates DNA.
Wilson MR, Jiang Y, Villalta PW, Stornetta A, Boudreau PD, Carrá A, Brennan CA, Chun E, Ngo L, Samson LD, Engelward BP, Garrett WS, Balbo S, Balskus EP
Science. 02 2019
COMMENT: This study reveals that the genotoxin colibactin from E. coli present in the gut alkylates DNA in vivo and might contribute colorectal cancer development and progression.
To obtain information about the active genotoxin’s chemical structure and its mode of action, we sought to identify and structurally characterize colibactin-DNA adducts from human cells infected with pks+ E. coli.
We discovered two adenine adducts that were specific to the cells exposed to pks+ E. coli. These adducts were confirmed to be pks-associated (...) Because these adducts are too small to derive from the final colibactin structure, we hypothesize that they arise from de- composition of a larger, unstable colibactin-DNA interstrand cross-link. Using a CometChip assay, we detected interstrand cross-link formation in cells infected with pks+ E. coli at the same time point at which we identified the characterized DNA adducts, supporting this proposal.
Our results provide direct evidence that the gut bacterial genotoxin colibactin alkylates DNA in vivo, providing mechanistic insights into how colibactin may contribute to CRC (...) The colibactin-derived DNA adducts we identified could serve as a biomarker of pks+ E. coli exposure and will ultimately help to address the question of whether DNA damage inflicted by colibactin-producing gut bacteria contributes to CRC development and progression in humans.