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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells
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Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells

机译：致癌细菌病原体幽门螺杆菌在其宿主细胞中触发DNA双链断裂和DNA损伤反应

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The bacterial pathogen Helicobacter pylori chronically infects the human gastric mucosa and is the leading risk factor for the development of gastric cancer. The molecular mechanisms of H. pylori-associated gastric carcinogenesis remain ill defined. In this study, we examined the possibility that H. pylori directly compromises the ■genomic integrity of its host cells. We provide evidence that the infection introduces DNA double-strand breaks (DSBs) in primary and transformed murine and human epithelial and mesenchymal cells. The induction of DSBs depends on the direct contact of live bacteria with mammalian cells. The infection-associated DNA damage is evident upon separation of nuclear DNA by pulse field gel electrophoresis and by high-magnification microscopy of metaphase chromosomes. Bacterial adhesion (e.g., via blood group antigen-binding adhesin) is required to induce DSBs; in contrast, the H. pylori virulence factors vacuolating cytotoxin A, y-glutamyl transpepti-dase, and the cytotoxin-associated gene (Cag) pathogenicity island are dispensable for DSB induction. The DNA discontinuities trigger a damage-signaling and repair response involving the sequential ataxia telangiectasia mutated (ATM)-dependent recruitment of repair factors—p53-binding protein (53BP1) and mediator of DNA damage checkpoint protein 1 (MDC1)—and histone H2A variant X (H2AX) phosphorylation. Although most breaks are repaired efficiently upon termination of the infection, we observe that prolonged active infection leads to saturation of cellular repair capabilities. In summary, we conclude that DNA damage followed by potentially imprecise repair is consistent with the carcinogenic properties of H. pylori and with its mutagenic properties in vitro and in vivo and may contribute to the genetic instability and frequent chromosomal aberrations that are a hallmark of gastric cancer.
机译：细菌性病原体幽门螺杆菌可长期感染人类胃粘膜，是胃癌发展的主要危险因素。幽门螺杆菌相关的胃癌发生的分子机制仍然不清楚。在这项研究中，我们研究了幽门螺杆菌直接损害其宿主细胞基因组完整性的可能性。我们提供的证据表明，感染在原代和转化的鼠类和人类上皮细胞与间充质细胞中引入了DNA双链断裂（DSB）。 DSB的诱导取决于活细菌与哺乳动物细胞的直接接触。通过脉冲场凝胶电泳和中期染色体的高倍放大显微镜观察核DNA的分离，即可发现与感染相关的DNA损伤。需要细菌粘附（例如通​​过血型抗原结合粘附素）来诱导DSB;相比之下，幽门螺杆菌毒力因子空化细胞毒素A，γ-谷氨酰转肽酶和细胞毒素相关基因（Cag）致病岛对于DSB诱导是必不可少的。 DNA不连续性触发损伤信号和修复反应，涉及顺序性共济失调性毛细血管扩张突变（ATM）依赖性募集修复因子-p53结合蛋白（53BP1）和DNA损伤检查点蛋白1（MDC1）和组蛋白H2A变体的介体X（H2AX）磷酸化。尽管大多数中断可在感染终止后得到有效修复，但我们观察到长时间的主动感染会导致细胞修复能力饱和。总而言之，我们得出的结论是，DNA损伤后可能进行不精确的修复与幽门螺杆菌的致癌特性及其在体内和体外的诱变特性相一致，并且可能导致遗传不稳定和频繁的染色体畸变，这是胃癌的标志。癌症。

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