Radiosensitivity of human genome

This project proposal consists of two distinct parts relevant to radiosensitivity: one dealing with the association between repair of DSBs and telomere maintenance, and another dealing with the relative biological effectiveness (RBE) of densely ionizing radiations. Physiological loss of telomere function is associated with cell senescence, which in turn activates DNA damage response. Dysfunctional telomeres lead to generation of genomic aberrations and contribute to major steps of carcinogenesis. Since telomere maintenance in Fanconi anemia (FA) primary cells has not been extensively examined, the main aim of this project is to evaluate the telomere capping function in order to determine if telomere dysfunction could be used as a biomarker of cellular radiosensitivity. Primary cells of FA patients (FANCA, FANCD2) and normal fibroblasts (NHDF) will be studied. The proposed investigation will give insight into the mechanisms underlying the intriguing radiosensitivity found in FA, where a marked clinical radiosensitivity is accompanied by normal cellular sensitivity of somatic cells. For investigating the effects of high LET radiations, accelerated protons and carbon ions will be used, and their effects on melanoma HTB140 and non-small lung cancer cell lines (NSCLC) studied. To overcome the radioresistance of malignant cells, we intend to investigate the impact of high LET irradiation combined with chemical modulating agents.