The hTERT alpha splice variant is a dominant negative inhibitor of telomerase activity

The telomerase catalytic subunit (hTERT) is an essential component of the h oloenzyme complex that adds telomeric repeats to the ends of human chromoso mes. Maintenance of telomeres by telomerase or another mechanism is require d for cell immortalization, and loss of telomeric DNA has been proposed as a trigger for cellular senescence. Available evidence suggests that regulat ion of telomerase activity primarily depends on transcriptional control of hTERT. However, several human tissues as well as some normal cell strains h ave been shown to express low levels of hTERT mRNA even though they lack te lomerase activity. We have previously identified six splice variants of hTE RT, including a "deletion" variant (hTERT alpha) that is missing conserved residues from the catalytic core of the protein. Several of the deletion va riants have been detected in normal and developing human tissues. We now sh ow that hTERT alpha inhibits endogenous telomerase activity, which results in telomere shortening and chromosome end-to-end fusions. Telomerase inhibi tion induced a senescence-like state in HT1080 cells and apoptosis in a jej unal fibroblast cell line. These results suggest a possible role for hTERT splice variants in the regulation of telomerase activity.