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芬科尼贫血路径修复了由菌素诱导的DNA跨链交叉链接

Maria Altshuller¹, Xu He¹, Elliot J MacKrell¹

¹Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.

Nature communications

|November 26, 2025

概括

科利巴克是一种肠道细菌毒素,会导致与结直肠癌相关的DNA损伤. 这项研究揭示了细胞如何修复这种损伤,涉及Fanconi贫血路径和特定的聚合酶,导致突变.

科学领域:

分子生物学分子生物学
遗传学遗传学是一个
癌症研究癌症研究

背景情况:

科利巴克是一种由肠道细菌产生的基因毒素,与结直肠癌的发展有关.
它通过在相反的DNA链上化脱氧腺素形成DNA链间交叉链 (ICL).
解决ICL的细胞机制存在,但它们在胆固醇菌素耐药性中的作用尚不清楚.

研究的目的:

为了研究大肠杆菌素诱导的ICLs的复制合修复.
为了识别参与耐受 colibactin DNA 损伤的细胞通路.

主要方法:

在体外研究中使用了Xenopus蛋提取物.
分析了复制分叉停滞和DNA修复途径激活.
研究了特定DNA聚合酶在转化合成中的作用.

主要成果:

在 colibactin ICLs 停滞的复制分叉激活了 Fanconi 贫血 (FA) 途径.
通过核溶解切口,FA 途径解开了 ICL,从而产生 DNA 双链断裂和单向导.
通过Pol η和Pol κ-REV1-Pol ζ复合物的转化合成 (TLS) 修复了单添加管,导致T>A突变.

结论:

建立了一个分子框架,以了解细胞对菌素诱导的ICL的耐受性.
确定了参与处理这种基因毒素的关键修复途径和TLS聚合酶.
提供了关于胆肠杆菌素在结直肠癌发生中的作用背后的机制的见解.

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