Influence of Kv11.1 (hERG1) K+ channel expression on DNA damage induced by the genotoxic agent methyl methanesulfonate

Abstract

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.

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Acknowledgments

We thank the expert technical contribution of Teresa González. EAG held a Ph.D. Bridge B fellowship from the University of Oviedo. The authors would like to acknowledge the technical support provided by the Scientific-Technical Services (SCTs) of the University of Oviedo.

Funding

LMS pertains to the Mass Spectrometry & Biomedical Analysis group of the University of Oviedo and was supported by Grant MINECO CTQ2016-80069-C2-1-R from the Ministerio de Economía y Competitividad of Spain. FB and PdlP work at the Hormone Receptors and Ion Channels group of the University of Oviedo and were supported in part by Grant BFU2015-66429-P (MINECO/FEDER UE) from the Spanish Ministerio de Economía y Competitividad, co-financed with European Fund for Economic and Regional Development (FEDER) funds.

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Fernández-Villabrille, S., Álvarez-González, E., Barros, F. et al. Influence of Kv11.1 (hERG1) K+ channel expression on DNA damage induced by the genotoxic agent methyl methanesulfonate. Pflugers Arch - Eur J Physiol 473, 197–217 (2021). https://doi.org/10.1007/s00424-021-02517-2

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Keywords

  • hERG channel
  • Kv11.1
  • Methyl methanesulfonate
  • DNA damage
  • Apoptosis
  • Cell cycle progression
  • Cell viability
  • PARP1 gene expression
  • Clonogenic efficiency