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A New Paradigm for Radiation-Induced Persistent Cellular Stress and Genomic Instability in Lung Carcinogenesis

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[Technical Report, Annual Report]

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Emory University

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We study cellular stress responses to sublethal doses of 1 or 2 Gy X-Rays that persist for up to a week in cultures of an immortalized normal bronchial epithelial cell line, HBEC3KT. We have found that p38MAPK is a driver and genomic instability and cell transformation an outcome of these responses, thus potentially involved in the development of radiogenic cancer. Further studies into these responses revealed altered levels of ubiquitination associated to chromatin, which can be modulated by interfering with p38MAPK activity. The goal of this project is to evaluate whether dysregulated chromatin ubiquitination is involved in driving persistent genomic instability and is the target for p38MAPK regulation. The main findings of the concluding period are that the predominant usage of the homology dependent DNA repair pathway by irradiated cells is homeostatic as demonstrated by experiments of deubiquitinases overexpression. We also found that the cell cycle defects and HR usage are probably due to increased replication stress.

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  • Medicine and Medical Research

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[A, Approved For Public Release]