Single-Run Catalysis and Kinetic Control of Human Telomerase Holoenzyme

Genome stability in eukaryotic cells relies on proper maintenance of telomeres at the termini of linear chromosomes. Human telomerase holoenzyme is required for maintaining telomere stability in a majority of proliferative human cells, making it essential for control of cell division and aging, stem cell maintenance, and development and survival of tumor or cancer. A dividing human cell usually contains a limited number of active telomerase holoenzymes. Recently, we discovered that a human telomerase catalytic site undergoes catalysis-dependent shut-off and an inactive site can be reactivated by cellular fractions containing human intracellular telomerase-activating factors (hiTAFs). Such ON-OFF control of human telomerase activity suggests a dynamic switch between inactive and active pools of the holoenzymes. In this review, we will link the ON-OFF control to the thermodynamic and kinetic properties of human telomerase holoenzymes, and discuss its potential contributions to the maintenance of telomere length equilibrium. This treatment suggests probabilistic fluctuations in the number of active telomerase holoenzymes as well as the number of telomeres that are extended in a limited number of cell cycles, and may be an important component of a fully quantitative model for the dynamic control of telomerase activities and telomere lengths in different types of eukaryotic cells.