Composition and function of telomeric multi-protein complexes and their regulation by ADP-ribosylation

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Telomere maintenance is vital to genome stability. The Shelterin complex, composed of six different proteins, protects telomeres from an illicit DNA damage response and orchestrates telomere extension by telomerase. The precise mechanisms of telomere protection and length homeostasis are incompletely understood. How does the cell navigate the dilemma that chromosome termini are sequestered from the DNA-damage sensing machinery to avoid lethalchromosome fusions whilst needing to be exposed to telomerase for telomere extension? In human cells, the ADPribosyltransferase tankyrase modifies Shelterin to enable telomerase-dependent telomere extension, presumably bymodulating Shelterin stoichiometry. In this project, we aim to combine biochemical, biophysical, single-molecule fluorescence and cell-based studies to understand the relevance and regulation of Shelterin complex stoichiometryin telomere protection and length homeostasis.