Stem cells can protect their chromosome ends without a protein that every other cell type in the body absolutely requires to survive. This discovery upends a long-standing dogma in cell biology. For decades, researchers believed that the protein TRF2 was essential for capping chromosome ends—called telomeres—in all cells. Without it, chromosomes fuse together, triggering cell death. But the team found that mouse embryonic stem cells lacking TRF2 divide normally and show no chromosome fusions. Only when those stem cells differentiate into specialised cell types do they suddenly become dependent on TRF2. This reveals a fundamental difference in how pluripotent and somatic cells handle chromosome end protection—a gap in knowledge the project now aims to fill. The researchers will use genetics, proteomics, and super-resolution microscopy to uncover how stem cells achieve end protection without TRF2. They will also build artificial telomeres in the lab using purified proteins to watch, in real time and at the single-molecule level, how telomere loops assemble, how telomerase is recruited, and how shelterin proteins interact with chromatin. This is fundamental science. It does not have an immediate practical application. But understanding how stem cells protect their genomes differently from other cells could, in the long term, inform strategies for regenerative medicine, ageing research, and cancer—where telomere maintenance is often hijacked to enable uncontrolled cell division.
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Telomeres have evolved to protect linear chromosome ends, preventing them from degradation and activating DNA damage response (DDR) pathways. Essential for "end protection" is the Shelterin subunit, TRF2, which inhibits the DDR and facilitates T-loop formation to sequester the telomere end, thereby hiding it from promiscuous DNA repair. The essentiality of "end protection" is revealed upon removal of TRF2, which triggers the DDR and rapid telomere-telomere fusions mediated by end joining. While dependency of "end protection" on TRF2 has been seen in numerous somatic cell types, we recently discovered that TRF2 is dispensable for "end protection" in stem cells and early development. Trf2-/- stem cells proliferate normally and remain free from telomere fusions, but rapidly switch to become reliant on TRF2 to prevent end-to-end fusions upon differentiation and loss of pluripotency. These findings challenge current dogma and reveal fundamental differences in "end protection" between pluripotent and somatic cell states. In this ERC proposal, we will exploit genetic, proteomic and super-resolution imaging methods to address how end protection is achieved in pluripotent cells, how this differs from somatic cells, and why different cell states have evolved distinct end protection mechanisms? To further our understanding of telomere maintenance mechanisms, we will also exploit our recent advances in biochemistry and single molecule (SM) biophysics to reconstitute telomeres in vitro. Using fluorescently labelled Shelterin, telomerase and telomere-associated factors, we will interrogate the mechanism of 1) T-loop assembly/disassembly, 2) telomerase recruitment to telomeres, and 3) Shelterin-chromatin interactions at telomeres. Our multi-disciplinary approach will establish the mechanistic basis of telomere end protection in pluripotent cells and will provide unprecedented insight into telomere maintenance mechanisms in real-time and at a SM level.
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