STRUCTURE/FUNCTION STUDIES ON HUMAN TELOMERASE

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The research plan proposed here is designed to allow me to use my post-doctoral training experience in molecular biology and reverse transcriptase mechanism, in conjunction with my pre- doctoral education in mutagenesis, to develop my independent career in cancer research. The planned project will afford me the unique opportunity to make a successful transition into cancer research by allowing me to use the extensive experience I have acquired in HIV reverse transcriptase biochemistry and apply it to telomerase research. Part of the training experience will involve collaboration with Dr. Ron Depinho, an acknowledged expert in the field of cancer research. Further intellectual exposure will come from interactions with AECOM Cancer Center investigators. Courses and seminars at AECOM will complement these interactions. A key role for telomerase reverse transcriptase (TERT) has recently been established in events that initiate the processes of transformation and oncogenesis. This makes it is both a central player in these processes and a potential target for therapeutic intervention of cancer. Therefore, it is important to functionally characterize TERT, to learn its mechanism of action, identify factors that modify its activity and to delineate functional domains and key residues critical for its activity. The proposed research will involve the study of human telomerase in an attempt to determine structure/function relationships. This will be accomplished through comparative biochemical analysis between reconstituted hTERT and cellular extracts of native hTERT, identification of functionally important residues in hTERT via site-directed mutagenesis, and, examination of the biological activity of hTERT mutants to establish their biological relevance.