Dottorato in SCIENZE DELLA VITA

Titolo della tesi: Low dose g-radiation protects Drosophila melanogaster chromosomes from double strands breaks and telomere fusions

In the last decades, radiation biology research has been focused on understanding the potential risks and benefits induced by the low-dose/dose-rate (LDDR) of ionizing radiation on public health. Despite a large number of studies, whether LDDR represents a hazard for humans is still continuously debated. Model organisms are considered valuable systems to reveal insight into this issue. I found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by either a 10Gy -radiation or treatment with radiomimetic bleomycin, is significantly reduced (~50%) when flies are chronically exposed to a previous dose of 0.4Gy -radiation delivered at a dose rate of 2.5mGy/h. This indicates that the protracted exposure to LDDR can induce a protective effect against DNA damage in Drosophila somatic tissues. Moreover, the F1 (but not F2) progeny of LDDR chronically exposed flies, is also resistant to -ray induced DNA damage indicating that the LDDR-mediated protective effect is epigenetically transmitted at least to one generation. My western blot and cytological analyses revealed that this effect is associated with changes in the dynamics of recruitment of H2Av, the Drosophila ortholog of mammal H2AX, at DNA damage sites. Interestingly, I also found that in Drosophila mitotic cells the 0.4Gy (2.5mGy/h) LDDR -radiation exposure reduces the frequency of telomere fusions (TFs) associated with the loss of telomere capping. This observation implies that in fruit flies the protracted exposure to LDDR can also induce a protective response on chromatin sites that are inappropriately recognized as DNA breaks. In addition, RNA sequencing and genetic data demonstrate that the LDDR-mediated effect on CBs is associated with a reduction of the Loquacious D (Loqs-PD) isoform, a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Thus, my work indicates that Loqs is a unique example of an LDDR-responsive gene that could shed light on the molecular bases of LDDR-mediated protective effects on a complex organism. Furthermore, my results reveal that modulation of siRNA represents an unanticipated epigenetic route to guarantee genome integrity in Drosophila mitotic cells.