Biologically Significant Damage in DNA

描述（由申请人提供）：生物的独特方面

DESCRIPTION (PROVIDED BY APPLICANT):The unique aspect of the biologically significant DNA damage associated with ionizing radiation is that this damage is clustered. It is therefore qualitatively distinct from that produced by UV radiation, or chemicals such as alkylating agents. The long-term goals of this work are to clarify the radiation chemical mechanisms by which DNA damage is introduced by ionizing radiation and by which it may be processed, modified, or repaired. This provides a means to evaluate the ability of cellular systems to cope with this damage. Applications to human health include defining the causes of individual variation in radiosensitivity (for example the role of anti-oxidants in protecting against radiation damage) and the development of mechanistic models for risk estimation of cancer etiology by low dose and low dose rate exposures. Our approach uses model systems in which DNA damage is detected as single strand breaks, double strand breaks, various base damages, and by its effect on the transformation efficiency of bacteria. The DNA substrates are plasmids and the SV4O minichromosome. The ionizing radiations include 7-rays and a-particles. To assess DNA damage, we will employ three new model systems that we have developed. These systems have been designed with the intention of concentrating upon the direct effect (ionization of the DNA itself), because this process is poorly understood in comparison with the indirect effect (DNA damage by solvent radicals). These model systems involve the use of DNA in the form of partially hydrated films, the reaction of DNA with one-electron oxidants, and the use of DNA in a highly associated form. Because the DNA damage is produced under well-defined conditions, a quantitative description of it can be made in terms of rate constants, lifetimes, and cluster sizes. The result will be an improved understanding of the mechanisms by which damage is introduced by energy deposition, is clustered and modified, leads to permanent products, and ultimately leads to biological and physiological endpoints.