A High Throughput Screen for Telomerase Assembly (RMI)

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Telomerase is a ribonucleoprotein complex that is specialized for the synthesis of the DNA found on the 3 strand at the end of each chromosome. Telomerase activity is elevated in most cancerous cells while it is absent in most undiseased tissues. Furthermore, inhibiting telomerase activity inhibits growth of cultured cancer cells and prevents growth of human tumors xenografted in mouse models. Thus, telomerase inhibitors have the potential of universal applicability as anticancer therapeutics, and the potential of telomerase inhibition as an anticancer approach has been validated by several approaches. Recently, additional roles for telomerase in promoting tumorigenicity and inhibiting apoptosis have been identified. These roles are independent of DNA synthesis, suggesting that inhibitors of only telomerase enzymatic activity will not achieve the maximum potential effect of telomerase-targeted therapeutics. In this proposal, a new technology platform for inhibiting telomerase activity will be described. The central hypothesis for the experiments is that the in situ generation of a dominant negative telomerase complex will provide a mechanism to disrupt all telomerase-dependent cellular functions. We have developed an assay to follow assemblage of telomerase by observing the association of specific parts of the telomerase complex that are required for telomerase activity. Specific Aim 1 describes efforts to generate a high throughput screen using scintillation proximity assay to report on these essential macromolecular interaction. Specific Aim 2 outlines a secondary screen to further evaluate hits. The completion of these studies will provide a novel HTS that will allow compounds that specific block proper assemblage of the telomerase holoenzyme complex to be identified. Such compounds will serve as leads for anticancer drug discovery and biological studies that illuminate the physiological role of telomerase in mediating tumorigenicity.