Defining the macromolecular structure of human telomeres

Objective

Telomeres safeguard chromosome ends and are essential for genome stability and human health. Telomere maintenance is orchestrated by the shelterin complex, which protects telomeres from DNA damage responses while regulating telomerase access. However, how shelterin balances these dual functions through its distribution along telomeric chromatin remains unknown – a critical gap in telomere biology and cancer research, since dysregulation of telomere maintenance drives tumorigenesis. TeloScope will generate the first multiscale structural model of telomeres in intact human cancer cells. Building on my recently developed cell lines with endogenously HaloTagged shelterin proteins, I will combine super-resolution microscopy to map shelterin distribution along telomeric chromatin with nanoscale precision and cellular cryo-electron tomography to resolve shelterin-bound telomeric chromatin ultrastructure. This unique strategy will reveal how shelterin coordinates telomere protection and elongation, uncovering telomere-specific vulnerabilities exploitable for first-in-class cancer therapeutics and providing a transferable framework to study chromatin-associated protein complexes in their native context. Therefore, TeloScope directly supports the EU Health Cluster, Mission on Cancer, and Europe’s Beating Cancer Plan, and reinforces Europe’s mission-driven research agenda. Hosted at Masaryk University in the lab of Prof. Jiří Fajkus laboratory, a world-leading expert in telomere biology and chromatin structure, I will gain advanced training in quantitative imaging, structural biology, and career development. A secondment in Dr. Kelly Nguyen lab (MRC Laboratory of Molecular Biology, UK) will provide complementary expertise in cryo-electron tomography of telomeres and expand my international network. Together, this interdisciplinary training and collaboration will position me to launch an independent research program in Europe and advance telomere-targeted cancer innovation.