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The Role of Telomerase  and Telomerase Reverse Transcriptase..

The Mechanics of Telomerase and Telomere Lengthening

Telomere biology and telomerase have been widely studied since the discovery of the telomere in the late 1970s. At the time of this writing, the PubMed database at the U.S. National Institutes of Health records 8,255 publications regarding telomerase.

In 2001, Sierra Sciences discovered a repressor binding site (dubbed "Site C") that blocks the expression of telomerase reverse transcriptase ("TERT"). This was a result of extensive research on the minimized human telomerase promoter region involving 118 deletions and hundreds of point mutations..

Deleting or alterating bases on this region of DNA will de-repress the expression of telomerase in a human cell. A drug that affects a protein binding to this site could theoretically have the same effect. Sierra Sciences is undertaking a drug discovery effort to find such a compound..

Sierra Sciences holds U.S. patent #6,686,159 for Site C, and U.S. patent #7,279,328 for a related repressor bind site, "GC-Box 5."

The Mutant hTR Assay:

In 2005, Sierra Sciences discovered methods of assaying TERT promoter modulatory agents, allowing the company to efficiently check a variety of compounds to see if they inhibit repression of hTERT.

Telomerase normally adds bases to the end of a chromosome in the normal telomere sequence, "TTAGGG." We discovered that if the RNA component of telomerase was manipulated to cause the enzyme to add bases in the sequence "CTAGCG," expression of telomerase would strongly inhibit cell growth.

By comparing the effect of a non-toxic compound on normal cells and on cells expressing mutant hTR, we were able to determine whether the compound caused the expression of hTR: if cell growth was normal in the wild-type cells and strongly inhibited in the mutant cells, the compound was a candidate for being a drug that causes telomerase expression.