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Influence of genome architecture on the induction of damage in DNA by UVA, and the repair of that damage


Sunlight is one of the major genotoxic threats in our environment. A great deal of previous work has uncovered the molecular pathways involved in the induction of damage in DNA by the UVB and UVC components of sunlight, and how that damage is repaired. I n contrast, much less is known about the effects of UVA even though recent epidemiological studies show that exposure to UVA correlates with the development of skin cancer. The object of this project is to understand how the higher-order structure of the genome influences the way damage in DNA is induced by UVA irradiation, and how that damage is repaired. UVA induces DNA damage indirectly via cellular sensitizers to generate reactive oxygen species that have a short diffusional range; as a result, the da mage must lie close to the sensitizers. However, the molecular nature of these sensitizers remains unknown, and so the first goal of this project is to identify the intra-nuclear structures that contain the sensitizers by localizing DNA damage relative to known structures within nuclei. In vitro tests with fractionated nuclear extracts will help to identify these structures and to verify results obtained by imaging. The organization of the chromatin fibre is also known to influence repair; therefore, a s econd part of the project will involve an analysis on how that organization influences induction and repair. Finally, I will try to transfer results obtained with cell cultures to a skin culture model that has more relevance to human epidemiology.

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