Design of Novel Molecules That Regulate Telomerase
We used the 3-dimensional structure of the catalytic subunit of telomerase to identify novel target binding sites essential for telomerase ribonucleoprotein assembly and activity. Telomerase adds multiple identical repeats of DNA (telomeres) to the 3’-end of eukaryotic chromosomes thus providing the genomic stability required for cell survival. There is now clear evidence that links telomerase to both cancer and aging. For example 90% of human cancers show high levels of activity of this enzyme when such activity is absent in most healthy tissues. The absence of telomerase activity (in adults) in healthy tissues leads to loss of ~50-100 bases of telomeric DNA with every cell division. When telomeres reach a critically short length, cells enter a permanent state of dormancy to prevent genomic instability, a process known as senescence, the hallmark of aging. Our goal is to identify compounds that regulate telomerase function that can be used to combat cancer and age related diseases.