Abstract
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.
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Acknowledgements
I would like to thank Dr. Zouhair Atassi for inviting me to write this article and his patience. I want to dedicate this article to Dr. Woodring Wright, who passed away over a year ago (in 2019). The biophysical analysis of the telomere/telomerase system was done by a former graduate student, Dr. Mohammed Sayed who worked in two laboratories, and a postdoctoral scientist, Dr. Ao Chen. I am grateful to Dr. Wright for his support and patience when we entered into a new direction. If we really learned anything new from this collaboration, it owed a lot to him. I would like to thank Dr. Jerry Shay for his continued trust in us as well as his enthusiasm and support in this line of research. Our studies were supported by grants from CPRIT (RP120474) and Welch Foundation (I-1684), startup funds from both the UT Southwestern Medical Center at Dallas and the IFAS at the University of Florida, and a 2019 pilot grant from the Office of Research at the University of Florida.
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Jiang, QX. (2021). Single-Run Catalysis and Kinetic Control of Human Telomerase Holoenzyme. In: Atassi, M.Z. (eds) Protein Reviews. Advances in Experimental Medicine and Biology(), vol 1371. Springer, Cham. https://doi.org/10.1007/5584_2021_676
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