The long-term goal of this project is to develop C. elegans as a model system for studying telomerase and telomere biology. Telomerase maintains chromosome integrity by adding de novo telomere repeats to chromosome termini. Most human somatic cells lack telomerase and display telomere erosion as they proliferate, which can lead to critical telomere shortening and senescence. We propose to study a promiscuous DNA replication process that may promote large-scale subtelomeric genome duplications at critically shortened telomeres. This process may be broadly relevant in genome evolution and could contribute to tumorigenesis. We hypothesize that telomere dysfunction can activate one or more stress response pathways that 1) may trigger systemic effects on organismal physiology that could contribute to aging or age-related diseases, 2) may promote survival in the absence of telomerase via a telomerase-independent telomere replication pathway termed Alternative Lengthening of Telomeres (ALT). A long-standing hypothesis in the field of chromosome biology is that aspects of genome evolution could be an orchestrated response to stress. The proposed studies will address this hypothesis in the context of telomere biology using a metazoan model system where a variety of conserved stress response pathways have been well characterized and where powerful genetic, cell biology and genomic tools are available: the nematode C. elegans.
Human somatic cells are deficient for telomerase and although telomere erosion can trigger senescence, the proposed studies will address a stress response pathway that is stimulated by telomere dysfunction and has systemic effects on physiology in the metazoan C. elegans, potentially revealing a central mechanism by which chromosome ends potentiate the aging process. We will also test the hypothesis that the activity of a stress response pathway promotes the telomerase- independent telomere maintenance mechanism ALT, which may occur in 10% of all human tumors and is not well understood. Finally, we address a promiscuous DNA replication process that may commonly occur during tumor development to create numerous genome rearrangements, some of which may be recurrent and could contribute to tumorigenesis.
