Identification of Proteins Essential for Telomere Elongation

A critical challenge in creating novel therapeutic agents in the treatment of breast cancer is the identification of cellular processes and molecular targets that differentiate normal and neoplastic tissue. One of the most consistent changes to occur n breast cancer is cellular immortalization through the upregulation of hTERT, which encodes the catalytic subunit of the telomerase ribonucleoprotein holoenzyme. Recently, we have identified the RNA binding domain of hTERT, and found that small substitutions to this region impede the binding of the hTR telomerase template RNA, and completely abrogate telomerase catalytic activity, thus defining and attractive region of hTERT that might be targeted for therapeutic targets. Interestingly, I have shown that this region of the protein also binds the endogenous inhibitor Pinxl. I have demonstrated that the mechanism of PinXl action may be distinct from inhibition of hTR binding, thus defining a separate mechanism for telomerase inhibition. We plan to identify molecules that bind hTERT and inhibit its action through displacement of hTR binding, to generate lead compounds that might be exploited for telomerase inhibition in cancer cells.