Mechanic studies of radical-induced DNA damage

点击翻译按钮获取中文摘要

DNA consists of two anti-parallel polynucleotide strands in a double helix, composed of repeating bases (G,C,A,T) interconnected by sugar-phosphate units. DNA is not a stable molecule. It is constantly under attack by free radicals generated within cells as a result of using oxygen as a terminal electron acceptor in respiration. In addition, DNA is a critical target for ionizing radiation (X-rays, charged particles), ultraviolet light, and diverse chemical oxidants. The reaction of free radicals and oxidants with DNA results in a multitude of different modifications, which ultimately determines its potentially deleterious effects. This research proposal deals with the chemical mechanisms of formation of DNA damage. Although the majority of studies have focused on free radical reactions of simple nucleic acid subunits, it is clear today that the fate of radicals leading to DNA damage is determined by the local helical structure of DNA polymers. When reactive species are attached to DNA, they have a tendency to react with neighboring base and sugar units to give novel types of damage involving in certain cases the formation of a covalent bond between two DNA bases. My objective over the next 5 years is to elucidate the mechanisms of DNA damage induced by reactive nitrogen species of one of the four bases of DNA, adenine. Recently, we developed a novel system to generate reactive species of adenine in DNA in which a stable precursor molecule of the reactive species is first incorporated into DNA and then it is activated by light or ionizing radiation. This method allows us to control the nature and initial position of reactive species in DNA. Our research program will help understand novel mechanisms of DNA damage, the influence of the double stranded helix on these reactions, and possibly assist in the development of drugs that target and sensitize cellular DNA to radiation.