Ionizing radiation-induced clustered DNA damages are postulated as critical damages producing lethal and mutagenic effects in humans. Clustered damages are defined here as two or more DNA damages (oxidized bases, abasic sites, single strand breaks) on opposing strands within a few helical turns. Recently, non-double strand break clustered damages have been shown to comprise more than 80 percent of the complex damages induced in DNA in solution by ionizing radiation. However, their actual biological roles are unknown because of the lack of a method for measuring them in genomic DNA. Using a method recently developed in this laboratory for quantifying clustered damages, this project will study induction and repair of clustered DNA damages in mammalian cells, specifically focusing on Determination of the basic biochemistry of clustered damages in cells: composition and levels, Characterization of repair of clustered damages in normal mammalian cells, and Evaluation of the impact on cluster repair of overproduction or deficiencies (including the use of knock-outs) in repair of lesions comprising the cluster. Clustered damages may be key lesions that produce adverse effects of ionizing radiation on humans. Deficiencies in their repair could be related to human diseases known to involve both radiation sensitivity and poor metabolism of oxidative damages, such as Cockayne syndrome and ataxia telangiectasia. Further, knowledge of conditions affecting formation of clustered damages, and cellular paths for dealing with them could allow the design of more effective radiation therapies.
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