The ribonucleoprotein enzyme telomerase plays a major role in the cellular homeostasis and its regulation is believed to be one a key step in malignant transformation. This project seeks to study the structures of two regions from human telomerase RNA (hTR) with the long-term goal of presenting a framework from which drugs that fight cancer may be discovered. Protein accessory factors that interact with, and stabilize, one of these two domains will also be studied. The primary technique proposed is Nuclear Magnetic Resonance spectroscopy (NMR), which can be used to determine at atomic resolution the contacts formed within a biomolecule, such as a domain of hTR, and between molecules such as between hTR and the accessory protein NHP2. The specific domains to be studied are the 60-nucleotide CR4/CR5 domain of hTR that is crucial for activation of the telomerase holoenzyme, and the box H/ACA snoRNA-like domain. This second domain interacts with the four protein factors (Nhp2, Nop10, Gar1, and Diskerin) that stabilize hTR in vivo. Obtaining the structures of these domains would provide crucial insight into telomerase function and ultimately allow for the design of drugs that can interact with the RNA and thus attenuate tumor growth.
