Brégeon Damien, Doddridge Zara A, You Ho Jin, Weiss Bernard, Doetsch Paul W
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Mol Cell. 2003 Oct;12(4):959-70. doi: 10.1016/s1097-2765(03)00360-5.
Cells exposed to DNA damaging agents in their natural environment do not undergo continuous cycles of replication but are more frequently engaged in gene transcription. Luciferase gene expression analysis with DNA templates containing uracil or 8-oxoguanine, placed at a defined position, indicated that in nondividing Escherichia coli cells, efficient mutagenic lesion bypass does occur in vivo during transcription. Sequence analyses of the transcript population revealed that RNA polymerase inserts adenine opposite to uracil, and adenine or cytosine opposite to 8-oxoguanine. Surprisingly, deletions were also detected for 8-oxoguanine-containing templates, indicating RNA polymerase slippage over this lesion. Genetic analyses showed that, in E. coli, 8-oxoguanine is subject to transcription-coupled repair. Consequently, DNA damages alter transcription fidelity in vivo, which may lead to the production of mutant proteins that have the potential to change the phenotype of nondividing cells.
在自然环境中暴露于DNA损伤剂的细胞不会经历连续的复制周期，而是更频繁地参与基因转录。对含有尿嘧啶或8-氧代鸟嘌呤且位于特定位置的DNA模板进行荧光素酶基因表达分析表明，在不分裂的大肠杆菌细胞中，转录过程中确实会在体内发生高效的诱变损伤旁路。对转录本群体的序列分析显示，RNA聚合酶在尿嘧啶对面插入腺嘌呤，在8-氧代鸟嘌呤对面插入腺嘌呤或胞嘧啶。令人惊讶的是，对于含8-氧代鸟嘌呤的模板也检测到了缺失，这表明RNA聚合酶在该损伤处发生了滑动。遗传分析表明，在大肠杆菌中，8-氧代鸟嘌呤会受到转录偶联修复。因此，DNA损伤会改变体内转录保真度，这可能导致产生具有改变不分裂细胞表型潜力的突变蛋白。
