The majority (>85%) of cancers rely on the ribonucleoprotein enzyme telomerase to catalyse the addition of telomeric DNA repeats to counteract telomere shortening, thus conferring cells with an unlimited replicative lifespan. While the catalytic function of telomerase is well reported, there is growing evidence for a number of non-canonical functions of telomerase, and more specifically the protein hTERT, that do not require its catalytic activity. One of these includes a protective function for telomerase in protecting the ends of chromosomes from DNA damage.
We have observed that over-expression of a catalytically inactive hTERT (D712A hTERT) in immortal GM639 fibroblasts can reduce the number of telomere dysfunction induced foci (TIFs) in comparison to cells transfected with an empty vector control, to a level similar to that observed in cells over expressing wild-type (WT) hTERT. In addition, over-expression of the β-deletion splice variant of hTERT (which encodes a truncated protein that is catalytically inactive) also resulted in a reduction in TIFs. The over-expression data was further validated through knock-down studies, where transfection of siRNA targeting hTERT resulted in a significant increase in TIFs. Furthermore, over-expression of the DAT122 hTERT mutant, which does not localise to telomeres, demonstrated a similar rescue of TIFs. This suggests that hTERT does not require recruitment to the telomere for its telomere-protective function, and potentially activates another signalling pathway that provides protection indirectly. These data suggest that hTERT may possess a protective function, independent of its catalytic activity, which signals through a telomere-independent pathway to protect immortal cells from telomeric DNA damage.