-Telomeres play important roles in carcinogenesis. Critically short telomeres or improperly capped telomeres are sensed as DNA breaks leading to cell cycle arrest and cell senescence. Thus, most cancers reactivate telomerase, which is normally silent in somatic cells, to sustain cell proliferation. Short and uncapped telomeres are also subjected to inappropriate DNA repair leading to telomere fusions. The dicentric chromosomes generated by telomere fusions can cause chromosome breakage during anaphase promoting tumor development.Despite the importance in cancer biology, the mechanisms underlying telomere capping are not fully understood. My research activity is aimed at filling this gap and is focused on the identification and characterization of Drosophila proteins required for telomere protection. The main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini and in the different mechanism of elongation. However, the two types of telomeres share many proteins. This suggests that the identification of additional Drosophila telomeric factors might lead to the discovery of novel human telomere components. The functional characterization of these factors in both flies and human is likely to generate synergistic information that will help decipher their respective roles at telomeres and to have an impact on cancer prevention and therapy.
-Myotonic dystrophy types 1 and 2 (DM1 and DM2) are autosomal dominant disorders characterized by muscle weakness, myotonia, progressive muscle degeneration and cataracts.DM2 is caused by an expansion of the tetranucleotide repeat CCTG within the first intron of CNBP, although the mechanism by which this expansion causes DM2 is unclear. Conflicting studies have suggested two models for the possible pathogenic mechanisms: 1) a gain-of-function RNA mediated mechanism in which the repeats alter normal cellular processeswithout affecting CNBP expression; 2) an alternative model in which the repeat expansion impair CNBP expression and lead to a general decreased in protein translation.We found that mutant flies in which dCNBP expression is downregulated by its RNAi-mediated knockdownexhibit decreased viability and strong locomotion defects, resembling the typical phenotypes of DM2. We plan to use this disease-model for the dissection of the fundamental molecular and cellular mechanisms of the disease and in genetic screens aimed at the identification of novel dCNBPinteracting genes implicated in DM2.
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