Mechanisms for Radiation Damage to DNA: LET Effects

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Our overall research goal is to elucidate fundamental mechanisms of radiation damage to DNA by radiations of varying linear energy transfer (LET). Our comprehensive model for DNA radiation damage that describes events from the formation of the initial DNA ion radicals, to hole and electron transfer, finally to molecular products will be tested at each step to elucidate the fundamental processes for DNA radiation damage. These studies, which are performed under conditions that emphasize the direct effect of radiation, will employ magnetic resonance spectroscopies, density functional theory and product analysis techniques as well as gamma and cyclotron heavy ion beam irradiations. There are five aims: First is the characterization of electron and hole transport in DNA which will concentrate on the role of electron transfer through the stacked bases, to intercalated species of known redox potential. The hypothesis that hole transfer localizes multiple oxidative damage sites to single a guanine base and thereby provides a radioprotective effect will also be tested. In our second aim, we will make use of an experimental breakthrough that allows for scavenging of holes and electrons in irradiated DNA providing for the isolation of the neutral (mainly sugar) radicals and the facile investigation of the nature and identity of these species. For the first time, it may be possible to identify and quantitate a number of immediate strand break processes from the direct effect at the radical stage. Our third aim will test mechanisms of sugar radical formation likely with high LET irradiation by an investigation of cationic radical excited states within DNA and components. Our fourth aim will use magnetic resonance techniques to characterize radicals (ESR, ENDOR) and to ascertain their spatial distribution and clustering (PELDOR) as a function of the LET of the radiation along the radiation track. Our ability to capture both holes and electrons allows us, now, to isolate and compare low and high LET generated neutral radicals. Our final aim will employ theoretical calculations to further test and confirm molecular mechanisms proposed in the above studies. Of prime interest will be a test via density functional theory of the hypotheses that low energy electrons cause immediate strand breaks. We believe this focused, collaborative effort will allow us to establish new understandings of fundamental radiation processes for biomedical research.