| Deoxyribonucleic Acid (DNA) is the most important molecule in a cell. It is the blueprint containing all information for the functioning of the vast majority of living cells. This information is passed on from one generation to the next through the replication of a cell's DNA. Consequently damage to DNA is a significant issue, and cells have a variety of mechanisms to maintain the fidelity of their DNA. In this thesis, I have examined the effect of one of the major agonists responsible for damage to DNA--ultraviolet (UV) light. With the declining amounts of ozone in the upper atmosphere, an increasing amount of solar UV light is reaching the earth's surface, which in turn is causing increasing concerns about DNA damage.; The effect of UV light on DNA is concentrated primarily on the base thymine. UV irradiation causes thymine to undergo a variety of changes, most of which have a common motif--the saturation of the 5,6-double bond of the base. While the formation and repair of the most common UV-induced damage products, the cyclobutane thymine dimer, has been extensively studied, others have not received as much scrutiny. In particular, I have focused on the formation and repair of the second most common UV-induced thyminyl lesion, the (6-4) photoproduct. This lesion is repaired by the recently discovered enzyme (6-4) photoproduct DNA photolyase. One mechanism proposed for the repair of the (6-4) photoproduct by this enzyme involves an unstable oxetane intermediate. I have synthesized stable compounds which are models of the natural oxetane, and have shown that these compounds can be converted to their constituent parts under conditions by which the enzyme is thought to operate, thereby providing a measure of support for the proposed mechanism.; I have also examined the effect that the saturation of the 5,6-double bond has on the single electron reduction potentials of a series of thymine derivatives. This research is important in understanding the effect of the 5,6-saturated bond motif. In addition, single electron reduction is a process performed by a number of enzymes in repairing this type of damage. Finally, I have also synthesized and crystallized a novel thymine-adenine photoproduct. This is the first reported crystal structure of a mixed pyrimidine-purine photoproduct. |
