Artificial DNA Framework Channel Modulates Antiapoptotic Behavior in Ischemia-Stressed Cells via Destabilizing Promoter G-Quadruplex

Regulating folding/unfolding of gene promoter G-quadruplexes (G4s) is important for understanding the topological changes in genomic DNAs and the biological effects of such changes on important cellular events. Although many G4-stabilizing ligands have been screened out, effective G4-destabilizing ligands are extremely rare, posing a great challenge for illustrating how G4 destabilization affects gene function in living cells under stress, a long-standing question in neuroscience. Herein, we report a distinct methodology able to destabilize gene promoter G4s in ischemia-stressed neural cells by mitigating the ischemia-induced accumulation of intracellular K⁺ with an artificial membrane-spanning DNA framework channel (DFC). We also show that ischemia-triggered K⁺ influx is positively correlated to anomalous stabilization of promoter G4s and downregulation of Bcl-2, an antiapoptotic gene with neuroprotective effects against ischemic injury. Intriguingly, the DFC enables rapid transmembrane transport of excessive K⁺ mediated by the internal G4 filter, leading to the destabilization of endogenous promoter G4 in Bcl-2 and subsequent turnover of gene expression at both transcription and translation levels under ischemia. Consequently, this work enriches our understanding of the biological roles of endogenous G4s and may offer important clues to study the cellular behaviors in response to stress.