Catalytically inactive telomerase in oncogenesis

Ends of human chromosomes called telomeres are essential for their structural and functional stability [1]. However, these DNA structures designed to function via a plethora of proteins and RNA molecules that bind them, encounter progressive shortening with each cell division due to the end replication problem. Terc, a long non coding (lnc)RNA and the reverse transcriptase TERT which uses Terc as primer to extend telomeric DNA are the core components of an enzyme called telomerase which keeps telomere lengths intact in rapidly proliferating stem cells [2]. In contrast, this telomere directed reverse transcriptase activity of telomerase is virtually non-existent in most mammalian somatic cells, as the expression of the TERT subunit is transcriptionally shut off in these cells [3]. However rapidly dividing cells such as those from upto 90% of human cancers rely on telomerase activity to elongate telomeres for proliferation. It is believed that a critical length of telomeres is necessary for capping these structures, preventing genomic instability and subverting cell death or senescence, in cancer cells. Hence transcriptional reactivation of TERT, is critical for reconstitution of telomerase activity and cancer progression [2, 3]. Once reactivated, the telomerase enzyme is believed to primarily regulate oncogenesis via telomere elongation. However, there are several reasons to believe that reactivated TERT and hence reconstituted telomerase do not merely rely on their role on telomeres in promoting oncogenesis. It was shown that alternate lengthening of telomeres (ALT), which can also maintain sufficient telomere lengths in cancer cells, is incapable in functionally replacing telomerase in oncogenic processes [4, 5]. Ectopic expression of TERT in mice (which unlike humans possess long telomeres) leads to enhanced tumor progression, without appreciable effects on telomeres. Most strikingly, lack of telomerase leads to repression of spontaneous tumorigenesis and human cancer cells show dramatic inhibition of growth when hTERT levels are reduced for even a few days, not enough time for a significant shortening of telomeres. Taken together, these and many other similar studies suggest that telomerase can regulate oncogenesis independent of telomeres elongation [4, 5]. Clearly, understanding these roles, evidence for which has been accumulated by various labs and across systems, is of paramount interest. Several components of the telomerase holoenzyme complex have been implicated in various oncogenic processes including DNA damage response, regulation of p53 and RNA dependent RNA polymerase activity. However, which of these activities mediate key telomere independent roles of telomerase in oncogenesis? Are the roles …