Ricerc@Sapienza

Eukaryotic cells evolved telomeres, specialized nucleoproteic complexes, to protect and replicate chromosome ends. In most organisms, telomeres consist of short, repetitive G-rich sequences added to chromosome ends by a reverse transcriptase, called telomerase. Specific DNA-binding protein complexes associate with telomeric sequences allowing cells to distinguish chromosome ends from sites of DNA damage. When telomeres become dysfunctional, either through excessive shortening or due to loss of proteins that preserve their function, they eventually lead to the activation of cell cycle checkpoints and/or to end-to-end fusion that ultimately give rise to chromosome breakage during anaphase. These events that in mammals might lead to several diseases including cancer clearly indicate that telomeres play critical roles in the maintenance of genome stability. Emerging data suggest a functional link between epigenetic marks and telomere homeostasis although most mechanisms underlying this connection are not known. Our preliminary results on the telomeric role of either Drosophila Pendolino (a conserved E2 variant ubiquitin-conjugating enzyme) or Eff, the fly ortholog of UbcH5B ubiquitin-conjugating enzyme in promoting histone methylation and Heterochromatin Protein 1 (HP1) ubiquitination, respectively, suggest that these proteins are indeed good candidates for the study of the conserved epigenetic regulation of telomere maintenance. In this regard, we propose to use D. melanogaster and A. thaliana, two model systems in which the epigenetics of telomere is well established, as well as human cells to tackle 3 main tasks: Assessing the roles of Peo (a) and its human ortholog AKTIP (b) in histone methylation at telomeres; (c) Studying the role of Eff/UbcH5B in the regulation of telomere protection in Drosophila, mammalian and plants. We believe that our results will highlight new pathways in the epigenetic regulation of telomere protection also for humans.