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Elevated activity of telomerase holoenzyme is important for a majority of human cancer cells because they need it to maintain length equilibrium of the telomere sequences at the ends of their linear chromosomes and thus their genome stability. Telomerase activity is equally important for most of normal dividing cells and stem cells. Gradual loss of telomeres is a hallmark for cellular aging (senescence), which endows telomerase activators with the potentialof anti-aging therapeutics. Elevated telomerase activity has been reported in 85-90% of human cancer, suggesting that its suppression be a generic anti-cancer treatment. Throughout the cell cycle, telomerase activity varies in different phases, and appears the highest in late Sphase as expected. How telomerase is regulated during cell division is thus a critically important question, but remains incompletely understood. Recently we uncovered a surprising ON-OFF control mechanism for human telomerase holoenzymes isolated directly from cancer cells. We found that a telomerase active site turns off after its processive extension of a DNA substrate, and the inactive catalytic site of the enzyme can be re-activated by intracellular telomerase-activating factors (iTAFs). We identified fast- and slow-acting active sitesin the native telomerase holoenzyme, and elucidated that both types of active sites are under the same ON-OFF control, suggesting that it is a fundamental property of the native telomerase. Our data further suggested that a dimeric telomerase holoenzyme contains one fast and one slow active site, and these two sites function in tandem, instead of in parallel. I will discuss the experimental studies that lead to these new findings and the possible contributions of the ON-OFF control to telomere length maintenance in normal and cancerous cells.
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