As a pediatric oncologist, I have an intense interest in novel targets for cancer-related therapy. My interest in telomere biology arises from a significant body of work that indicates telomeres are of central importance to the processes of immortalization and tumorigenesis. Experiments in yeast, and recently in human cell lines, have firmly established a causal link between telomere length and lifespan. Furthermore, a majority of tumors exhibit activation of telomerase, raising the question whether telomerase can be exploited as a chemotherapeutic target. Other recent studies, however, have shown that telomerase-negative mise are capable of forming tumors, and tumor cell lines can utilize telomerase-independent pathways for telomere maintenance, thereby highlighting the importance of a thorough understanding of telomere dynamics if considering the introduction of anti-telomerase agents into the clinical arena. The aim of this proposal is to advance our understanding of telomere biology by the characterization of two activities, the Ku complex and the protein Cdc13p, which appear to play a role in mediating the telomere function of protecting chromosomal ends. These studies will be performed in yeast, which has proven to be a valuable model system for the rapid identification and evaluation of genes which can be extrapolated to the study telomere biology in humans. The Ku heterodimer, previously characterized for its role in double-standard DNA break repair and V(D)J recombination in mammalian cells, has also been shown to play a role in telomere maintenance and chromatin structure in yeast. Classical genetics will be utilized to identify and analyze mutants in the Ku complex which have uncoupled telomere and DNA repair function. These mutants will then be exploited to identify potential new proteins which interact with the Ku heterodimer in telomere maintenance. Ku, the newly identified Ku-associated proteins and Cdc13p will be further analyzed for their in vivo association with telomeric chromatin and how their associations are affected by different genetic backgrounds. Additionally, the role of these proteins in the regulation the terminal telomere structure, the G-tail, will be investigated. These studies, in addition tp addressing important questions in telomere end protection, will provide me with a firm foundation in classical genetics and modern molecular biology on which to build a career in molecular oncology. Dr. Lundblad's laboratory in the Department of Molecular and Human Genetics at the Baylor College of Medicine provides an excellent environment in which to develop my scientific skills.