Speaker: Professor Matthew Comstock, Michigan State University

Fundamental processes of life are carried out within cells by nanometer-scale molecular machines. Understanding how these tiny machines work reveals the basic physical underpinnings of life and can provide opportunities for technological and medical advances. The field of single-molecule biophysics uses powerful experimental methods, such as optical tweezers and single-molecule fluorescence, to directly observe the actions of individual molecules in real time. In this talk I will share the results of such an investigation of the human telomerase molecular machine. This protein-RNA hybrid machine is crucial to maintaining our chromosomes during replication as it appends a long, unique sequence of DNA to the chromosome ends (i.e., telomeres) that allows the ends to ‘hide’ (within the shelterin structure). Telomerase is essential for both the survival of continuously dividing stem cells (relevant to aging) but also the proliferation of aggressive cancers. How exactly the machine can function, repeatedly recycling and resetting its built-in RNA template on the end of the DNA, without ‘walking the plank’, i.e., falling off the end of the DNA, remains an essential mystery. We recently developed a method utilizing high-resolution optical tweezers that allowed us to directly observe the step-by-step, stochastic, processive activity of human telomerase synthesizing DNA on the end of a model chromosome (Patrick et al., Nature Chem Bio, 2020). In part, we revealed that the telomerase machine has a ‘safety harness’, an anchor site binding and intermittently releasing the newly synthesized product DNA and allowing for risky DNA synthesis on the very edge of the chromosome.