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.