Molecular Mechanisms of Telomere Length Homeostasis

Project Summary Telomeres ensure genome integrity by facilitating chromosome end replication through telomerase, the activity of which enables cellular proliferation. Uncontrolled proliferation as may occur in cancer cells requires hyper-activation of telomere-extension activity. Conversely, lack of telomere extension results in degenerative disorders or premature aging. Critical to telomere structure and function, the conserved multifunctional shelterin complex associates with telomeres to coordinate multiple telomere activities. The long-term objective of our NIGMS MIRA research program is to determine, at the atomic resolution, molecular mechanisms of telomere length homeostasis through comprehensive biochemical, structural, and functional characterizations of the telomeric shelterin complex, shelterin-telomerase interactions, and telomerase biogenesis. Mutations in telomerase subunits or shelterin components have been increasingly linked to cancer and premature aging. Shelterin complex and shelterin-telomerase interactions play essential roles in regulating synthesis of telomeric DNA repeats and defining telomere lengths that support or restrict cell proliferation. Our recent efforts have achieved the conceptual advancement on the role of shelterin bridge, rather than individual shelterin component per se, in regulating telomere length and the landmark determination of the atomic views of shelterin bridge assembly process by x-ray crystallography. Our accumulated expertise and prior success position us to deepen our investigations. In the next five years, we aim to address the following three fundamental questions in the field: 1) Elucidate the biochemical and structural basis of the assembly of whole fission yeast shelterin complex and its role in telomere length control; 2) Determine the mechanistic basis of shelterin disassembly; 3) Determine the structural basis of telomerase RNA folding quality control mechanism by Pof8 complex. Accomplishment of the proposed studies will provide new and significant mechanistic insights into the maintenance of our chromosome ends and set up the foundation for the development of new therapeutic approaches against diseases caused by telomere dysfunction, such as premature aging.