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The DNA-end replication problem


Telomere Biology

Teresa Teixeira

NEW: Post-doctoral position available

Detailed information here.

The linear chromosomes of eukaryotes end with telomeres. Because of the inability of semi‐conservative DNA replication machinery to fully duplicate DNA ends, telomeres display a singular dynamic structure, providing both a mechanism to ensure the integrity of the genome and a mode of control of cell division in eukaryotes. Since telomeres physiologically shrink at each cell division, they are considered as molecular clocks for the counting of number of generations. Alterations in their equilibrium are thus found in human diseases like cancer and aging syndromes. Therefore, fundamental knowledge in telomere biology has consequently provided invaluable contributions, not only in basic matters of molecular genetics, but also in cellular aging and cancer transformation.

Despite an increasing knowledge in telomeres since their first description in the 1930's, and their molecular analysis since the 1980's, an ever more number of cellular pathways have been shown to interfere with their biology. How these pathways interconnect and how they specifically operate at telomeres remains unclear. The archetype of this is our incomprehension of how the semi‐conservative DNA replication machinery precisely processes the telomeres.

Our goal is to understand the mechanisms that have evolved to raise and maintain linear genomes, a hallmark of the Eukaryote kingdom. Currently, we focus on the study of the so‐called DNA end replication problem of DNA extremities and its consequence(s) at the cellular level. In an evolutionary perspective, we would like to understand how the rise of linear chromosomes underlies the possibility to control cell proliferation and the emergence of multicellularity.

In the team, we mainly use Saccharomyces cerevisiae as an experimental model. Currently, we focus on

        ‐the dissection of the structure of telomeres at the level of single‐molecules to fully describe the events occurring at the telomeres while they are replicated through the semi‐conservative DNA replication machinery, processed by the different DNA repairing activities and elongated by telomerase.

        ‐the understanding to which extent the mechanisms operating at the critically short telomere in telomerase‐negative cells shares similarities with the repair of DNA double‐strand breaks or the repair of stalled or collapsed DNA replication forks.

        ‐the link between the structure of the shortest telomere in the cell that initiates replicative senescence and cell proliferation capacity.

Laboratory of Molecular and Cellular Biology of Eukaryotes