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Cellular responses to DNA damage
The genomes of eukaryotic cells are under continuous assault by cosmic and terrestrial radiation sources, as well as the byproducts of the intracellular metabolism such as reactive oxygen species and replication errors that lead to the generation of DNA double strand breaks (DSBs). In addition to accidental events, DSBs are also generated during scheduled biological processes such as meiosis or V(D)J recombination and during diagnostic procedures utilizing ionizing radiation. Finally, therapeutic interventions in the therapy of cancer, such as exposure to ionizing radiation and treatment with certain chemotherapeutic agents, leads to the generation of DSBs. DSBs are severe lesions with a high probability of conversion to lethal or mutagenic events. Therefore, eukaryotic cells have developed efficient repair pathways to remove DSBs from their genome. These repair activities are supported by signaling pathways, termed checkpoints that register the presence of DSBs and arrest or delay cell cycle progression in G1, S, or G2 phase to prevent modifications compromising repair or generating lethal events. Research activities in our Institute focus on the evaluation of the relative contribution of the different pathways implicated in DSB repair, as well as on the elucidation of the contribution of checkpoints in this process. We investigate the contribution of homologous recombination repair (HRR) and non-homologous endjoining (NHEJ) in the repair of radiation induced DSBs and explore the possible function of alternative pathways of NHEJ that utilize PARP-1 and DNA Ligase III. Furthermore, we study checkpoint responses in bystander cells not directly hit by radiation, as well as checkpoint activation in cells exposed to high temperatures. Understanding cellular responses to DSBs at the molecular level will have important implications to our understanding of genomic instability and cancer, as well as in radiation protection and the improvement of cancer therapy by ionizing radiation or genotoxic drugs.