The primary goal of Project 1 is to find agents that counteract radiation-induced DNA deletions leading to cell death and genetic instability that can have long-term consequences such as birth defects and cancer. We have previously shown that DNA deletions are inducible by ionizing radiation in yeast and human cells, as well as in mice. We will use reporter assays in yeast and mice to identify agents that counteract the radiation-induced frequency of DNA deletions. We have developed a bioluminescent version of the yeast deletion assay that is suitable for automation to a high throughput screening (HTS) format.
In aim 1 we propose to characterize the effect of the chemicals of different compound library sets for their activity to counteract the cytotoxicity as well as the frequency of DNA deletions when added before or after treatment with ionizing radiation (Core D). The power of the yeast assay is that it can be used as an HTS assay to prioritize chemicals for further assays in mice and in human cells in aims 3 and 4 and in other Research Projects. Ionizing radiation induces these deletions also in a delayed fashion causing a persistent hyperrecombination phenotype, which is a major contributor to the progressive, multistage development of malignant disease.
For aim 2 we will reformat the HTS yeast assay of aim 1 and use a subset of agents selected from Aim 1 to specifically score their potential to counteract radiation-induced hyperrecombination.
In aim 3 we will use a subset of those chemicals that were most potent in aim 1 to determine whether they reduce the frequency of radiation-induced DNA deletions in vivo in mice (Core C). Finally, in aim 4 we will determine whether any of the three most potent radioprotectors from all three projects combined would reduce the frequency of radiation-induced tumors in mice. We will also determine effects of the agents selected from Aim 1 on levels of radiation-induced oxidative 8-oxoguanine DNA damage and strand breaks. Furthermore, lymphocytes of the mice treated with those chemicals that show an in vivo effect will be used in the Proteomics Core to determine the signaling pathways that they activate.
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