Grant: Operating Grant

One could compare our genome to an extraordinarily large library that contains numerous shelves, each with many books. The combined information contained in all the books represents our genetic information and is required to make us what we are. In this paraphrase, the bookshelves could be likened to our chromosomes. Due to a heavy use of the books and also because the whole library, including the shelves, need to be duplicated before each cell division, there is continued wear and tear on the terminal bookends on the shelves. Without continued upkeep and repair, the bookends eventually will become dysfunctional, causing books to fall off the shelves and get lost. The telomerase enzyme that we study basically is the repair enzyme for the bookends of the shelves, thus in real life it is essential to ensure the integrity of our chromosomes. Inside cells, telomerase is composed of a number of components but minimally, two of them are required for the enzyme to work: a protein and an RNA molecule. Inadequate supply of any of those components, causing instability of the chromosomes, is associated with a number of human disease states, foremost cancer, but also dyskeratosis congenita (DKC). In fact, it has been shown that DKC can be caused by mutations in the RNA component of telomerase. Using budding yeast as a model system, here we propose to investigate the biology of the telomerase enzyme. In particular, we wish to determine all the components of the yeast telomerase, learn more about how the RNA is regulated and localized and how the enzyme operates at its most important location, namely the catalytic center. Given the fact that telomerase function and regulation generally is very highly conserved across many species, including humans, we speculate that these studies provide critical clues and input into questions on how this enzyme affects human health.