Structure and Dynamics of Telomeres and Telomerase

Project Summary Telomeres are essential structures located at the ends of linear chromosomes that protect genomic integrity by preventing chromosomal fusion, degradation, and activation of DNA damage response pathways. The telomerase reverse transcriptase maintains telomere length to compensate for telomere erosion by adding short DNA repeat sequences to chromosome ends. In the absence of telomerase, telomeres progressively shorten with each cell division due to the end-replication problem and nucleolytic processing. Critically short telomeres ultimately induce cellular senescence or apoptosis. Dysregulation of telomere homeostasis has been implicated in many human diseases, including cancer and rare genetic syndromes. Yet, the molecular mechanisms underlying telomere/telomerase biology and the interplay between telomere dysfunction and disease pathology are still not fully understood. With our previous NIGMS funding, we investigated telomeres/telomerase from ciliates, yeasts, and vertebrates to uncover conserved structural features of telomerase RNA, protein subunits, and telomere DNA. We used a combination of biochemical, structural, computational, and novel single-molecule biophysical methods to study the function and dynamics of telomerase and telomere DNA. Our results, together with the progress made in other laboratories, advanced detailed mechanistic models for telomerase enzyme assembly, spatiotemporal regulation of telomerase recruitment to telomeres, telomere chromatin remodeling by shelterin proteins, and coordinated conformational changes within telomerase during its complex catalytic cycle. We are now uniquely positioned to critically evaluate these models with our established state-of-the-art methodologies. The insights gained from this research will provide a framework for the development of new therapeutic strategies and preventive measures for telomere-related disorders. Funding from the MIRA will provide the necessary resources and flexibility to pursue new avenues of mechanistic research within the rapidly developing field of telomere and telomerase biology.