Molecular Mechanisms of Nitroarene Toxicity

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DESCRIPTION (provided by applicant): Cancer is a general term that refers to more than a hundred of different diseases characterized by uncontrolled cell division and the capacity of these cells to invade and destroy surrounding normal tissues. Etiologically, cancer is a slow developing condition affected by multiple factors including exposure to environmental toxics, lifestyle, viral infections and individual genetic makeup. Known factors that increase cancer risk include tobacco smoke, exposure to UV or ionizing radiation, and the intake of environmental toxicants present in the air, water or foods. Nitroarenes are widespread pollutants found in cigarette smoke, coal fly ash, and diesel exhaust. These compounds react with cellular DNA forming bulky base lesions that can cause gene mutations and eventually trigger carcinogenic processes. The nucleotide excision repair (NER) system opposes these effects by removing bulky DNA lesions and restoring genome integrity. Xeroderma Pigmentosum and Cockayne syndrome, two genetic diseases caused by NER deficiencies, are flagrant examples of the damaging consequences that the persistence of DNA lesions have for human health. In this application, we plan to use a multidisciplinary approach to determine the molecular mechanisms that mediate the toxicity of 3-nitrobenzanthrone (3-NBA), a prevalent environmental toxicant. The guiding hypothesis of our proposal is that 3-NBA can form adducts that increase DNA stability without perturbing its structure. As a result, these lesions escape NER processing, persisting in DNA and extending their toxic effects. We will test our hypothesis by establishing the solution structure and thermodynamic parameters of duplexes having site specific adducts derived from 3-NBA (aim 2) and establishing their processing by the mammalian NER system (aim 3). As biological end-point, we will investigate the mutagenic potential of 3-NBA adducts and establish the mechanisms of trans-lesion synthesis in mammalian cells (aim 4). Chemical synthesis by which we develop methods for the preparation and site-specific incorporation of these adducts into 2'- oligodeoxynucleotides, is the foundation of our studies and forms an integral part of the proposal (aim 1). We expect that our multidisciplinary approach will define the relevant mechanisms of 3- NBA toxicity and, in turn, identify better biomarkers of environmental exposure and disease risk.