Telomere replication is mediated by telomerase, an RNA dependent DNA polymerase structurally similar to retroviral reverse transcriptases and viral RNA polymerases. Biochemical studies on telomerase for more than two decades have provided a wealth of information regarding telomerase function and substrate specificity. Despite this information, the biophysical mechanisms underlying telomerase architecture and function are poorly understood. Our goal is to further elucidate the molecular basis of telomere replication by telomerase using structural and biochemical approaches. The information generated here should provide novel insights into the basic mechanisms of telomere replication and length homeostasis. It will further enrich our understanding of the mechanism of DNA replication by polymerases in general. It will provide a framework to design small molecule inhibitors of telomerase that may be of therapeutic value for cancer and other diseases associated with cellular aging.
In recent years, a number of factors essential for telomerase regulation and telomere maintenance have been identified. The method by which telomerase and associated regulatory factors physically interact and function with each other to maintain appropriate telomere length is poorly understood. Structural and biochemical characterization of these factors, both in isolation and in complex with one another will facilitate our understanding of how the proper function of these factors impacts telomerase function and cell proliferation.