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RAD18在抑制致癌和瘤基因驱动突变的不同作用在活体中

Jay R Anand¹, Bethany Wagner¹, Jitong Lou²

¹Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

bioRxiv : the preprint server for biology

|July 9, 2025

概括

通过促进精确的DNA损伤修复,DNA修复蛋白RAD18可以抑制口腔癌. 缺乏Rad18会加速口腔瘤的发展,增加特定突变,但不会影响肺癌. 这突出了RAD18的重要性.

科学领域:

遗传学遗传学是一种遗传学.
癌症生物学癌症生物学
修复DNA修复DNA的修复

背景情况:

RAD18蛋白激活Y家族的跨损伤合成 (TLS) DNA聚合酶.
RAD18在癌细胞中过度表达和激活,但其在癌症基因组塑造和瘤发生中的作用尚不清楚.

研究的目的:

调查RAD18状态对化学诱导和瘤基因驱动的瘤发生的影响.
确定RAD18在口腔状细胞癌 (OSCC) 发育和基因组突变概况中的作用.
评估RAD18对Kras驱动的肺癌发生的影响.

主要方法:

在Rad18缺乏 (Rad18-/-) 和野生类型 (Rad18+/+) 小鼠中使用了一种4-尼托基诺林-1-氧化物 (4NQO) 诱导的口腔致癌模型.
分析了OSCC基因组的突变特征,特别是G(C)>T(A) 转变.
采用Kras ((G12D) 诱导的肺癌发生模型来评估Rad18缺乏的影响.

主要成果:

在慢性4NQO治疗后,与Rad18+/+小鼠相比,Rad18-/-小鼠的口腔瘤发病加速.
在Rad18-/-小鼠的OSCC基因组中增加了G(C)>T(A) 转变.
在Kras(G12D) 诱导的肺癌模型中,Rad18缺乏并没有显著改变瘤率,发病率或突变.

结论:

RAD18表现出特定于环境的瘤抑制活性,促进DNA损伤的无错绕道,并抑制口腔致癌.
RAD18可能会影响人类癌症基因组和瘤发生,特别是在与4NQO类似的环境暴露的背景下.

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