Linear chromosomes of eukaryotes end with telomeres that ensure their stability. Because of the inability of semi-conservative DNA replication machinery to fully replicate DNA ends, telomeres require dedicated mechanisms to be duplicated and their length is eroded at each cell division. For this reason, telomeres constitute molecular clocks that determine cell proliferation potential in eukaryotes. Strikingly, we have shown recently that it is the shortest telomere in the cell that determines the onset of replicative senescence. This project aims a complete and detailed dissection of the in vivo DNA-end replication problem and the deep understanding of its impact for cell division capability. Specifically my goals are (1) the determination of the exact structures that result from the replication of DNA extremities, (2) the examination of the activities operating at the shortest telomere that triggers replicative senescence and (3) the investigation of the correspondence between telomere molecular structure and cell proliferation state at individual cell scale. To achieve this, I will undertake in Saccharomyces cerevisiae original and innovative single-molecule and single-cell approaches, that, in combination with genome-wide screens and sophisticated cellular settings, will allow to track and challenge a specified telomere of defined length. I anticipate that this work will lead to an in-depth understanding of how telomeres are replicated and how they enable the control of cell proliferation in eukaryotic cells, a matter at the intersection of the fundamentals of molecular genetics, cell biology of aging and oncology.
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