Accumulation of abasic sites induces genomic instability in normal human gastric epithelial cells during Helicobacter pylori infection.
Accumulation of abasic sites induces genomic instability in normal human gastric epithelial cells during Helicobacter pylori infection.
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DOI：
10.1038/oncsis.2014.42
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发表时间：
2014-11-24
期刊：
影响因子：
6.2
通讯作者：
Sweasy, J. B.
中科院分区：
文献类型：
--
作者：
Kidane, D.;Murphy, D. L.;Sweasy, J. B.
幽门螺杆菌感染与炎症有关，导致活性氧和氮类（RON）的释放，引发宿主细胞中的DNA损伤。未修复的DNA损伤导致与癌症相关的基因组不稳定性。碱基切除修复（BER）是RON诱导的DNA损伤过程中维持基因组稳定性的关键，但其在H.幽门螺杆菌感染的正常胃上皮细胞。在这里，我们表明，在H。幽门螺杆菌感染后，无碱基（AP）位点积累并导致双链DNA断裂（DSB）水平增加。相反，OGG1 DNA糖基化酶的下调降低了H过程中AP位点和DSB的水平。幽门感染在细胞周期的不同阶段，AP位点的加工导致DSB水平的升高。因此，H.幽门螺杆菌和随后的BER在正常胃上皮细胞中的加工有可能导致基因组不稳定性，这可能在胃癌的发展中起作用。我们的研究结果是一致的解释，BER处理DNA损伤的精确协调是维持基因组稳定性的关键。
Helicobacter pylori infection of the human stomach is associated with inflammation that leads to the release of reactive oxygen and nitrogen species (RONs), eliciting DNA damage in host cells. Unrepaired DNA damage leads to genomic instability that is associated with cancer. Base excision repair (BER) is critical to maintain genomic stability during RONs-induced DNA damage, but little is known about its role in processing DNA damage associated with H. pylori infection of normal gastric epithelial cells. Here, we show that upon H. pylori infection, abasic (AP) sites accumulate and lead to increased levels of double-stranded DNA breaks (DSBs). In contrast, downregulation of the OGG1 DNA glycosylase decreases the levels of both AP sites and DSBs during H. pylori infection. Processing of AP sites during different phases of the cell cycle leads to an elevation in the levels of DSBs. Therefore, the induction of oxidative DNA damage by H. pylori and subsequent processing by BER in normal gastric epithelial cells has the potential to lead to genomic instability that may have a role in the development of gastric cancer. Our results are consistent with the interpretation that precise coordination of BER processing of DNA damage is critical for the maintenance of genomic stability.
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