DNA交联修复缺陷增强了人类细胞对大肠杆菌素诱导的遗传毒性的敏感性。

IF 1.9 4区 医学 Q2 GENETICS & HEREDITY
Masanobu Kawanishi, Osamu Tsubohira, Ai Ueshima, Yuuta Hisatomi, Yoshimitsu Oda, Michio Sato, Noriyuki Miyoshi, Michihiro Mutoh, Hideki Ishikawa, Keiji Wakabayashi, Takashi Yagi, Kenji Watanabe
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引用次数: 0

摘要

大肠杆菌素是一种小的基因毒性聚酮分子,由肠道细菌的一个子集产生,包括人类肠道微生物群中的某些大肠杆菌(E. coli)。它的生物合成是由聚酮合成酶(pks)基因簇编码的多步骤酶促过程控制的。大肠杆菌素被认为主要通过诱导DNA链间交联(ICLs)发挥其致癌潜力;然而,其遗传毒性的确切机制在很大程度上仍未得到解决。在这项研究中,我们关注ICL的形成及其相关的修复途径,以研究大肠杆菌素诱导的ICL是否在诱导染色体畸变和抑制细胞增殖中起核心作用。研究结果:HAP1细胞缺乏FANCD2 (ICL修复所必需的基因),它们的野生型对偶体被从日本结直肠癌(CRC)患者中分离出来的产大肠杆菌蛋白(clb +)大肠杆菌菌株感染。恢复培养后,评估微核(MN)细胞的频率。结果显示,与野生型细胞相比,fancd2缺陷细胞的MN细胞频率明显更高。此外,采用XTT法对clb +菌株的细胞毒性进行了评估。fancd2缺陷细胞对clb +大肠杆菌菌株的敏感性高于野生型细胞。结论:这些发现表明,clb + E. coli产生的大肠杆菌蛋白(colibactin)可以在icl的形成中发挥作用,从而在诱导染色体畸变和抑制人细胞增殖方面发挥重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
DNA cross-link repair deficiency enhances human cell sensitivity to colibactin-induced genotoxicity.

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.

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来源期刊
Genes and Environment
Genes and Environment Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.00
自引率
0.00%
发文量
24
审稿时长
27 weeks
期刊介绍: Genes and Environment is an open access, peer-reviewed journal that aims to accelerate communications among global scientists working in the field of genes and environment. The journal publishes articles across a broad range of topics including environmental mutagenesis and carcinogenesis, environmental genomics and epigenetics, molecular epidemiology, genetic toxicology and regulatory sciences. Topics published in the journal include, but are not limited to, mutagenesis and anti-mutagenesis in bacteria; genotoxicity in mammalian somatic cells; genotoxicity in germ cells; replication and repair; DNA damage; metabolic activation and inactivation; water and air pollution; ROS, NO and photoactivation; pharmaceuticals and anticancer agents; radiation; endocrine disrupters; indirect mutagenesis; threshold; new techniques for environmental mutagenesis studies; DNA methylation (enzymatic); structure activity relationship; chemoprevention of cancer; regulatory science. Genetic toxicology including risk evaluation for human health, validation studies on testing methods and subjects of guidelines for regulation of chemicals are also within its scope.
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