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首页> 外文期刊>DNA repair >2-AAF-induced tumor development in nucleotide excision repair-deficient mice is associated with a defect in global genome repair but not with transcription coupled repair.
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2-AAF-induced tumor development in nucleotide excision repair-deficient mice is associated with a defect in global genome repair but not with transcription coupled repair.

机译：2-AAF诱导的核苷酸切除修复缺陷小鼠的肿瘤发展与整体基因组修复缺陷有关，但与转录偶联修复无关。

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The nucleotide excision repair (NER) pathway comprises two sub-pathways, transcription coupled repair (TCR) and global genome repair (GGR). To establish the importance of these separate sub-pathways in tumor suppression, we exposed mice deficient for either TCR (Csb), GGR (Xpc) or both (Xpa) to 300 ppm 2-acetylaminofluorene (in feed, ad libitum) in a unique comparative exposure experiment. We found that cancer proneness was directly linked to a defect in the GGR pathway of NER as both Xpa and Xpc mice developed significantly more liver tumors upon 2-AAF exposure than wild type or Csb mice. In contrast, a defect in TCR appeared to act tumor suppressive, leading to a lower hepatocellular tumor response in Xpa mice (tumor incidence of 25%) as compared to Xpc mice (53% tumor-bearing mice). The link between deficient GGR and tumor proneness was most pronounced in the liver, but this phenomenon was also found in the urinary bladder. As tumor induction by 2-AAF appeared almost exclusively dependent on a defect in GGR, we examined whether gene mutation induction in the non-transcribed lacZ locus could reliably predict tumor risk. Interestingly, however, short-term 2-AAF exposure induced lacZ mutant levels in Csb mice almost as high as those found in Xpa or Xpc mice. This indicates that lacZ mutant frequencies are not correlated with a specific DNA repair defect and eventual tumor outcome, at least not in the experimental design presented here.
机译：核苷酸切除修复（NER）途径包括两个子途径：转录偶联修复（TCR）和全局基因组修复（GGR）。为了确定这些单独的子途径在肿瘤抑制中的重要性，我们将缺乏TCR（Csb），GGR（Xpc）或两者（Xpa）的小鼠暴露于300 ppm 2-乙酰氨基芴（饲料中，任意摄入）中比较暴露实验。我们发现，癌症倾向与NER的GGR通路的缺陷直接相关，因为Xpa和Xpc小鼠在暴露于2-AAF时比野生型或Csb小鼠明显发展出更多的肝肿瘤。相反，与Xpc小鼠（荷瘤小鼠53％）相比，TCR缺陷似乎具有抑制肿瘤的作用，从而导致Xpa小鼠的肝细胞肿瘤应答降低（肿瘤发生率为25％）。 GGR缺乏与肿瘤易感性之间的联系在肝脏中最为明显，但在膀胱中也发现了这种现象。由于2-AAF诱导的肿瘤几乎完全取决于GGR的缺陷，因此我们检查了非转录lacZ基因座中的基因突变诱导是否可以可靠地预测肿瘤风险。然而，有趣的是，短期2-AAF暴露在Csb小鼠中诱导的lacZ突变体水平几乎与Xpa或Xpc小鼠中发现的水平一样高。这表明lacZ突变体频率与特定的DNA修复缺陷和最终的肿瘤预后无关，至少在此处介绍的实验设计中不相关。

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