Figure 8: Schematic illustration of the telomerase inhibition and telomere uncapping induced by carboxylated SWNTs.

The telomere is postulated to form a lariat-like structure, in which the 3′-G-overhang of the telomere invades a duplex telomeric region to form a double-stranded T-loop and a single-stranded D-loop. During DNA replication, the 3′-overhang becomes accessible to telomerase to elongate telomeres. However, in the presence of carboxylated SWNTs, the C-rich telomeric strand self-assemble into an i-Motif structure, whereas the corresponding complementary G-rich strand adopts compact G-quadruplex, resulting in the block of telomere elongation by telomerase. The persistence of i-motif and G-quadruplex would lead to telomere uncapping and disrupt the telomeric loop structure, resulting in formation of anaphase bridges and telomere fusion, characteristics of telomere dysfunction. SWNTs also induce release of telomere-binding protein (TRF2, POT1 and PCBP1) from telomere and cause the degradation of telomeric 3′-overhang. The dysfunctional telomere elicits DNA damage response at telomeres and activates the DNA repair pathways, resulting in p16, p21-mediated cell cycle arrest, apoptosis and senescence to suppress further growth of genomically unstable cells.