Grant: Foundation Grant

One could compare our genome to a large library that contains numerous shelves, each with an extraordinary large number of books. The combined information contained in all the books represents our genetic information and is required to make us who we are. In this paraphrase, the bookshelves represent our chromosomes. Due to the heavy use of the books and because the whole library, including the shelves, need to be duplicated each time a cell divides, there is continued wear and tear on the terminal bookends on the shelves. Without continued upkeep and repair, the bookends will eventually become dysfunctional, causing books to fall off the shelves and get lost. The telomeres and the telomerase enzyme that we study are, respectively, the bookends and the maintenance operator for the bookends. In real life, it is essential to ensure the integrity of the ends of our chromosomes. The telomerase enzyme is composed of several subunits; two of which, one protein and one RNA molecule are required for the enzyme to work in a minimalistic test-tube system. Inadequate supply of any of the components, causing instability of the chromosomes, is associated with aging and human disease, foremost cancer, but also dyskeratosis congenita (DKC) and other congenital disorders now called telomeropathies. Using a simple but powerful model system, we propose to investigate the biology of telomeres and the telomerase enzyme. In particular, we plan to identify all the components, learn more about how they interact, are regulated and localized. Most importantly, we will determine when and how telomerase operates at its most important location, namely on telomeres. Given that telomere and telomerase function and regulation are highly conserved across many species, from yeast to humans, our studies will provide critical clues and input into how telomere biology could be exploited for the benefit of human health.