Besides their crucial role in cell electrogenesis and maintenance of basal membrane potential, the voltage-dependent K⁺ channel Kv11.1/hERG1 shows an essential impact in cell proliferation and other processes linked to the maintenance of tumour phenotype. To check the possible influence of channel expression on DNA damage responses, HEK293 cells, treated with the genotoxic agent methyl methanesulfonate (MMS), were compared with those of a HEK-derived cell line (H36), permanently transfected with the Kv11.1-encoding gene, and with a third cell line (T2) obtained under identical conditions as H36, by permanent transfection of another unrelated plasma membrane protein encoding gene. In addition, to gain some insights about the canonical/conduction-dependent channel mechanisms that might be involved, the specific erg channel inhibitor E4031 was used as a tool. Our results indicate that the expression of Kv11.1 does not influence MMS-induced changes in cell cycle progression, because no differences were found between H36 and T2 cells. However, the canonical ion conduction function of the channel appeared to be associated with decreased cell viability at low/medium MMS concentrations. Moreover, direct DNA damage measurements, using the comet assay, demonstrated for the first time that Kv11.1 conduction activity was able to modify MMS-induced DNA damage, decreasing it particularly at high MMS concentration, in a way related to PARP1 gene expression. Finally, our data suggest that the canonical Kv11.1 effects may be relevant for tumour cell responses to anti-tumour therapies.

除了它们在细胞生电和维持基底膜电位中的关键作用外，电压依赖性 K ⁺Kv11.1/hERG1 通道对细胞增殖和其他与维持肿瘤表型相关的过程具有重要影响。为了检查通道表达对 DNA 损伤反应的可能影响，将用基因毒性剂甲磺酸甲酯 (MMS) 处理的 HEK293 细胞与用 Kv11.1-永久转染的 HEK 衍生细胞系 (H36) 的细胞进行比较。编码基因，并在与 H36 相同的条件下获得第三个细胞系 (T2)，通过永久转染另一个无关的质膜蛋白编码基因。此外，为了深入了解可能涉及的规范/传导依赖性通道机制，使用特定的 erg 通道抑制剂 E4031 作为工具。我们的结果表明 Kv11. 1 不影响 MMS 诱导的细胞周期进程变化，因为在 H36 和 T2 细胞之间没有发现差异。然而，该通道的经典离子传导功能似乎与低/中 MMS 浓度下细胞活力降低有关。此外，使用彗星试验直接测量 DNA 损伤，首次证明 Kv11.1 传导活性能够改变 MMS 诱导的 DNA 损伤，尤其是在高 MMS 浓度下，以一种与PARP1基因表达。最后，我们的数据表明，经典的 Kv11.1 效应可能与肿瘤细胞对抗肿瘤疗法的反应有关。