Scholarlink

Introduction <p>Colibactin is a small genotoxic molecule of polyketide produced by a subset of enteric bacteria including certain <i>Escherichia coli</i> (<i>E. coli</i>) harbored in the human gut microbiota. Its biosynthesis is governed by a multistep enzymatic process encoded by the polyketide synthase (<i>pk</i>s) gene cluster. Colibactin is thought to exert its carcinogenic potential primarily through the induction of DNA interstrand crosslinks (ICLs); however, the precise mechanisms underlying its genotoxicity remain largely unresolved. In this study, we focused on ICL formation and its associated repair pathways to investigate whether colibactin-induced ICLs play a central role in the induction of chromosomal aberrations and inhibition of cell proliferation.</p> Findings <p>HAP1 cells deficient in <i>FANCD2</i>, a gene essential for ICL repair, and their wild-type counterparts were infected with colibactin producing (<i>clb</i>⁺) <i>E. coli</i> strains isolated from a Japanese colorectal cancer (CRC) patient. Following recovery culture, the frequency of micronucleated (MN) cells was assessed. The results showed that <i>FANCD2</i>-deficient cells exhibited a significantly higher frequency of MN cells compared to wild-type cells. Additionally, the cytotoxicity of the <i>clb</i>⁺ strains was evaluated using the XTT assay. <i>FANCD2</i>-deficient cells demonstrated higher sensitivity to the <i>clb</i>⁺ <i>E. coli</i> strains than wild-type cells.</p> Conclusion <p>These findings suggest that colibactin, produced by <i>clb</i>⁺ <i>E. coli</i>, can play a role in the formation of ICLs, thereby contributing significantly to the induction of chromosomal aberrations and the inhibition of human cell proliferation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

DNA cross-link repair deficiency enhances human cell sensitivity to colibactin-induced genotoxicity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月22日

查看全文
  • Masanobu Kawanishi,
  • Osamu Tsubohira,
  • Ai Ueshima,
  • Yuuta Hisatomi,
  • Yoshimitsu Oda,
  • Michio Sato,
  • Noriyuki Miyoshi,
  • Michihiro Mutoh,
  • Hideki Ishikawa,
  • Keiji Wakabayashi,
  • Takashi Yagi,
  • Kenji Watanabe

摘要

Introduction

Colibactin is a small genotoxic molecule of polyketide produced by a subset of enteric bacteria including certain Escherichia coli (E. coli) harbored in the human gut microbiota. Its biosynthesis is governed by a multistep enzymatic process encoded by the polyketide synthase (pks) gene cluster. Colibactin is thought to exert its carcinogenic potential primarily through the induction of DNA interstrand crosslinks (ICLs); however, the precise mechanisms underlying its genotoxicity remain largely unresolved. In this study, we focused on ICL formation and its associated repair pathways to investigate whether colibactin-induced ICLs play a central role in the induction of chromosomal aberrations and inhibition of cell proliferation.

Findings

HAP1 cells deficient in FANCD2, a gene essential for ICL repair, and their wild-type counterparts were infected with colibactin producing (clb⁺) E. coli strains isolated from a Japanese colorectal cancer (CRC) patient. Following recovery culture, the frequency of micronucleated (MN) cells was assessed. The results showed that FANCD2-deficient cells exhibited a significantly higher frequency of MN cells compared to wild-type cells. Additionally, the cytotoxicity of the clb⁺ strains was evaluated using the XTT assay. FANCD2-deficient cells demonstrated higher sensitivity to the clb⁺ E. coli strains than wild-type cells.

Conclusion

These findings suggest that colibactin, produced by clb⁺ E. coli, can play a role in the formation of ICLs, thereby contributing significantly to the induction of chromosomal aberrations and the inhibition of human cell proliferation.