良好控制的修复机制参与维持基因组稳定性,它们的失败会导致DNA异常并增加肿瘤风险。此外,肿瘤微环境,富含诱导氧化应激和影响细胞周期检查点的因素,当修复途径步履蹒跚时,会加剧DNA损伤。最近的研究揭示了某些细菌之间的关联,包括支原体,和各种癌症,致病机制正在积极调查中。我们之前证明了发酵支原体DnaK,HSP70家族伴侣蛋白,阻碍PARP1和p53等对基因组完整性至关重要的蛋白质的活性。此外,我们对其在人类癌细胞系中的相互作用组的分析揭示了DnaK与DNA修复机制的几个组成部分的参与。最后,在我们的实验室进行的体内实验,使用我们小组产生的DnaK敲入小鼠模型证明,DnaK暴露导致DNA拷贝数变异增加,表明基因组不稳定。我们在这里提供的证据表明,DnaK的表达与暴露于氨基甲酸乙酯后体内肿瘤的发病率增加有关。DNA损伤剂;ii)离体自发DNA损伤;iii)离体表达促炎细胞因子,活性氧水平的变化,和增加跨组织的β-半乳糖苷酶活性。此外,DnaK与着丝粒不稳定性增加有关。总的来说,这些发现强调了支原体DnaK在癌症和其他遗传疾病的病因中的重要性,为预防提供了一个有希望的目标,诊断,和治疗学。
Well-controlled repair mechanisms are involved in the maintenance of genomic stability, and their failure can precipitate DNA abnormalities and elevate tumor risk. In addition, the tumor microenvironment, enriched with factors inducing oxidative stress and affecting cell cycle checkpoints, intensifies DNA damage when repair pathways falter. Recent research has unveiled associations between certain bacteria, including Mycoplasmas, and various cancers, and the causative mechanism(s) are under active investigation. We previously showed that Mycoplasma fermentans DnaK, an HSP70 family chaperone protein, hampers the activity of proteins like PARP1 and p53, crucial for genomic integrity. Moreover, our analysis of its interactome in human cancer cell lines revealed DnaK\'s engagement with several components of DNA-repair machinery. Finally, in vivo experiments performed in our laboratory using a DnaK knock-in mouse model generated by our group demonstrated that DnaK exposure led to increased DNA copy number variants, indicative of genomic instability. We present here evidence that expression of DnaK is linked to increased i) incidence of tumors in vivo upon exposure to urethane, a DNA damaging agent; ii) spontaneous DNA damage ex vivo; and iii) expression of proinflammatory cytokines ex vivo, variations in reactive oxygen species levels, and increased β-galactosidase activity across tissues. Moreover, DnaK was associated with increased centromeric instability. Overall, these findings highlight the significance of Mycoplasma DnaK in the etiology of cancer and other genetic disorders providing a promising target for prevention, diagnostics, and therapeutics.