Grant: Project Grant

One could compare our genome to an extraordinarily large library that contains numerous shelves, each with many books. The combined information contained in these 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 regularly, there is continued wear and tear on the terminal bookends on the shelves. Without continued upkeep and repair, these bookends eventually will become dysfunctional, causing books to fall off the shelves and get lost. The telomeres and the telomerase enzyme that we study basically are represented by the bookends and the maintenance operator for the bookends on the shelves. However, much about the where, when and how of the maintenance mechanisms is very poorly understood. Yet, in humans, inadequate supply of any component of the bookends, causing instability of the chromosomes, is associated with a number of diseases, foremost cancer, but also dyskeratosis congenita (DKC). Using a simple eukaryote model system, we propose to investigate the molecular biology of the telomerase enzyme (the bookend maintenance operator). In particular, we wish to determine how all the components of it are put together, learn more about how they interact, are regulated and localized. Most importantly, we wish to know when and how telomerase operates at its most important location, namely on the telomeres, and thus will mount a defined system of telomerase action (bookend repair) in a test-tube. Given the fact that telomerase function and regulation are highly conserved from yeast to humans, we speculate that these studies provide critical clues and input into questions on how telomere biology could be exploited for the benefit of human health.