Colibactin 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.

中文翻译：

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Colibactin 衍生的链间交联的脱嘌呤。

Colibactin 是一种具有遗传毒性的肠道微生物组代谢物，长期以来一直被怀疑在结直肠癌中起病因学作用。有证据表明，大肠杆菌素在真核细胞中形成 DNA 链间交联 (ICL) 并激活 ICL 修复途径，导致产生 ICL 依赖性 DNA 双链断裂 (DSB)。在这里，我们展示了大肠杆菌素 ICL 可以直接进化为 DNA DSB。使用超螺旋质粒 DNA 的拓扑结构作为烷基化加合物稳定性的代表，我们发现大肠杆菌素衍生的 ICL 对 3' 磷酸的脱嘌呤和消除不稳定。这种 ICL 降解途径逐渐导致单链断裂 (SSB) 和随后的 DSB。ICLs 自发转化为 DSBs 与非同源末端连接修复缺陷细胞对产生大肠杆菌素的细菌敏感的发现一致。本文的结果完善了我们对大肠杆菌素衍生的 DNA 损伤的理解，并强调了 DSB 表型背后的复杂性。