Why do our cells age? Part of the answer is hidden at the very ends of our chromosomes, where telomeres are located.
These small structures act like protective caps: they prevent our DNA from being damaged when cells divide. But with each division, the telomeres shorten a little. When they become too short, the cell loses its ability to function properly, which is linked to aging and several diseases, including some cancers.
To slow down this process, cells have a crucial tool: telomerase. This enzyme is responsible for repairing and lengthening telomeres, thus helping to maintain cell health. Therefore, better understanding its function is a major challenge for aging research.
In a study published in the journal
Science, Cryo-electron microscopy structure of the budding yeast telomerase holoenzyme an international team of researchers composed of Raymund Wellinger, professor-researcher at the FMSS of the University of Sherbrooke, Pascal Chartrand, professor at the University of Montreal and Thi Hoang Duong Nguyen, from the Laboratory of Molecular Biology achieved a feat: identifying for the first time the atomic structure of yeast telomerase. While this organism may seem distant from humans, it is actually a model organism of choice in biology, because many fundamental mechanisms are similar to ours.
Thanks to state-of-the-art imaging technology, the research team discovered that yeast telomerase has a very complex architectural structure. At its center is a long piece of RNA that acts as a scaffold, holding together many proteins. Some are part of the very stable core, essential for the enzyme's activity, while others are attached more loosely, giving the whole assembly great flexibility.
Beyond the discoveries about the role of RNA, the study's results highlight that the protein Est3, a small factor specific to telomerase and previously poorly understood, plays a central role as a protein-protein interaction platform, stabilizing the entire telomerase. Disruption of Est3's interactions with other factors such as Est2 and Pop1 leads to telomere shortening and accelerated cell aging, demonstrating the functional importance of these contacts. The structure also confirms that Est3 is a structural homologue of a human telomeric protein that is part of telomeres.
Finally, a sub-complex of three proteins called Pop1/6/7, which is shared with RNA maturation enzymes, facilitates the association of three proteins essential for telomerase functions via combined RNA-protein interactions. Remarkably, the research team identified a specific loop of Pop1 necessary for maintaining telomeres, but dispensable for RNA maturation, demonstrating that Pop1 is a genuine telomerase subunit with a function specific to telomeres.
Beyond yeast, these results allow for a better understanding of how telomerase assembles and functions, even when it relies on a long, flexible, and complex RNA. The principles uncovered could apply to the telomerase of other species, as well as to other cellular structures containing long RNA molecules. The study finally shows how, over the course of evolution, different forms of organization have emerged across species, while preserving an essential function: protecting DNA and ensuring the proper functioning of cells, a central issue in aging and associated diseases.