DNA is the carrier of biological information and damage to DNA has been believed to be responsible for many diseases including aging and cancer. One electron oxidation by charge migration through DNA is one of the processes that lead to DNA damage. It is known that the guanine N1 imino proton can be transferred to the N3 of cytidine that is hydrogen bonded to it. Some reports have implication that this proton transfer and radical cation migration are coupled to each other. We have incorporated 5-fluoro-2 -deoxycytidine (F5dC) in place of normal dC in DNA duplexes. Although, the lower pKa of F5dC should perturb the proton transfer process from the guanine to it, we do not see any change in the charge migration ability compared to the strands having normal cytidines. However, there is a considerable decrease in the guanine damage, when there is F5dC opposite to it. These results indicate that the charge migration is not coupled with proton transfer process, but the change in basicity affects the reactivity of the guanine radical cation. We have also reported a systematic study on the charge migration through adenine (A) and thymidine (T) containing DNA strands. The damage has predominantly seen in thymidine, although from oxidation potentials reaction at adenine was expected. The thymidine reaction has been analyzed thoroughly. It has similar distance dependence property as the well known guanine damage. Study of thymidine damage in presence of radical scavengers, replacement of thymidines by Uracil and HPLC-MS study point toward reactions involving tandem lesion. On the basis of these information and molecular modeling study we have proposed a possible pathway leading to one-electron oxidation at the thymidines.
| Identifer | oai:union.ndltd.org:GATECH/oai:smartech.gatech.edu:1853/16203 |
| Date | 16 May 2007 |
| Creators | Ghosh, Avik Kumar |
| Publisher | Georgia Institute of Technology |
| Source Sets | Georgia Tech Electronic Thesis and Dissertation Archive |
| Detected Language | English |
| Type | Dissertation |
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