DNA damage and Autophagy

DNA damage and Autophagy Serena Galati1-2, Maria Carla Gerra1, Mirca Lazzaretti1and Annamaria Buschini1. 1Department of Life Sciences, University of Parma, Parma, Italy; 2Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia, Italy. Agents such as UV, IR, genotoxic chemicals and ROS could affect DNA integrity. Cells counteract their action through the induction of DNA repair systems and occasionally the activation of cell responses such as cell senescence and death. Autophagy is emerging to be linked to DNA damage response although its role is still not well known. We have analyzed the involvement of autophagy during the treatment of U937 cell line with chemicals that induce different injuries inside cells (cisplatin, menadione, EMS, bortezomib, bleomycin). To reach this goal we have analysed the toxic and genotoxic effect of each compound and of its combination with rapamycin and chloroquine, inducer or inhibitor of autophagy respectively. Activation of the autophagy was assessed by the use of a plasmid coding for the LC3-GFP protein. The cytotoxic effect of the chemicals on U937 cells was measured by MTS. Genotoxicity was evaluated by the Alkaline Comet Assay. Modulation of the autophagy brings, in almost all cases, to variation in the cyto- and geno-toxicity induced by the compounds. We have observed a dual role of autophagy in response to injuries: the activation of the pathway induces sometimes the reduction of the toxic potential of the compound and sometimes causes an increase of their toxicity. Dissecting the molecular pathways involved in the autophagy activation in response to DNA damage may open innovative strategies able to reduce toxicity of many compounds, including anticancer drugs.