Laboratory of Molecular Physiology and Biophysics and the Cryo-EM Center, Hauptman-Woodward Medical Research Institute, Buffalo, NY, USA.
Department of Materials Design and Innovation, and Department of Physiology and Biophysics, University of Buffalo, Buffalo, NY, USA.
Adv Exp Med Biol. 2022;1371:109-129. doi: 10.1007/5584_2021_676.
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.
真核细胞中的基因组稳定性依赖于线性染色体末端端粒的适当维持。人端粒酶全酶对于大多数增殖性人细胞中端粒稳定性的维持是必需的，这使其成为控制细胞分裂和衰老、干细胞维持以及肿瘤或癌症的发育和生存的关键因素。一个分裂的人类细胞通常包含有限数量的活性端粒酶全酶。最近，我们发现人类端粒酶催化位点经历依赖于催化的关闭，并且无活性位点可以通过包含人类细胞内端粒酶激活因子（hiTAFs）的细胞部分重新激活。这种人端粒酶活性的开-关控制表明全酶的无活性和活性池之间存在动态切换。在这篇综述中，我们将把开-关控制与人类端粒酶全酶的热力学和动力学特性联系起来，并讨论其对端粒长度平衡维持的潜在贡献。这种处理方法表明在有限数量的细胞周期中，活性端粒酶全酶的数量以及延伸的端粒数量存在概率波动，这可能是不同类型真核细胞中端粒酶活性和端粒长度动态控制的全定量模型的重要组成部分。
