bi9b01070_si_001.pdf (8.65 MB)
Depurination of Colibactin-Derived Interstrand Cross-Links
journal contribution
posted on 2020-02-12, 16:08 authored by Mengzhao Xue, Kevin M. Wernke, Seth B. HerzonColibactin is a genotoxic
gut microbiome metabolite long suspected
of playing an etiological role in colorectal cancer. Evidence suggests
that colibactin forms DNA interstrand cross-links (ICLs) in eukaryotic
cells and activates ICL repair pathways, leading to the production
of ICL-dependent DNA double-strand breaks (DSBs). Here we show that
colibactin ICLs can evolve directly to DNA DSBs. Using the topology
of supercoiled plasmid DNA as a proxy for alkylation adduct stability,
we find that colibactin-derived ICLs are unstable toward depurination
and elimination of the 3′ phosphate. This ICL degradation pathway
leads progressively to single strand breaks (SSBs) and subsequently
DSBs. The spontaneous conversion of ICLs to DSBs is consistent with
the finding that nonhomologous end joining repair-deficient cells
are sensitized to colibactin-producing bacteria. The results herein
refine our understanding of colibactin-derived DNA damage and underscore
the complexities underlying the DSB phenotype.
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Colibactin-Derived Interstrand Cross-Links Colibactineukaryotic cellsetiological roleICL degradation pathwayDNA DSBsnonhomologous endDSB phenotypecolorectal cancercolibactin-derived DNA damagealkylation adduct stabilitysupercoiled plasmid DNAcolibactin forms DNA interstrand cross-linkscolibactin-derived ICLsgenotoxic gut microbiome metabolitestrand breakscolibactin ICLscolibactin-producing bacteriarepair-deficient cellsactivates ICL repair pathwaysICL-dependent DNA double-strand breaksSSB
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