Rapid Telomere Reduction in Cancer Cells Induced by G-Quadruplex-Targeting Copper Complexes

Telomere length determines the replicative capacity of mammalian cells. Successive telomere reduction to a critically short length can lead to cellular senescence that irreversibly prevents cells from further cell division. A series of Cu complexes has been designed as selective artificial nucleases that degrade G-quadruplex telomeric DNA and exhibit selective DNA binding affinity and cleavage reactivity toward G-quadruplex telomeric DNA over duplex DNA. In contrast to protein-based nucleases that usually lack membrane permeability, significant cellular uptake and nuclear localization of these Cu complexes was observed. Rapid telomere reduction of cancer cells was also observed after only 1 day incubation, while the absence of DNA fragmentation indicates a low level of nonselective DNA cleavage. Robust telomere reduction by the designed Cu complexes is an S-phase-specific event that is associated with increased formation of the G-quadruplex structure during DNA replication.