DNA metilasyonunun DNA yapısı ve DNA-küçük molekül etkileşimi üzerindeki etkileri

Epigenetics is the field of science which investigates the heritable changes in DNA conformation, gene expression, and phenotype that are not related to DNA sequence. Epigenetic modifications are known to be associated with many different diseases including cancer. One of these modifications is the methylation of DNA at the 5th carbon of cytosine. Among different cancer types, the methylation level differs but the mechanism of this difference is not well-known. The increased stability of DNA, accompanied by the decreased flexibility is thought to be one of the contributing factors to this difference by affecting the gene expression. In this study, the effect of deoxy-5-methylcytosine (d5mC) on stability and secondary structure of double helical Dickerson dodecamer DNA (DDD) was examined systematically using UV-Vis and CD spectrophotometry. Within the context, DDDs with different number of d5mCs at different positions were compared. Our results revealed that while the location of d5mC does not affect the structure and stability of DDD, the increased number of d5mC substitutions changed the DNA conformation slightly and increased the stability. Moreover, the effect of DNA methylation on DNA-small molecule interactions was also investigated using DDD and DDD8, which has no and 8 d5mCs, respectively, as model systems. All the molecules, especially intercalators (although having lower binding affinities compared to groove binders), change the structure of DDD more than DDD8 but have more effect on the stability of DDD8 more than DDD. The gained stability of DNA in the presence of d5mC does not allow the structural alteration upon small molecule binding. This thesis opens a door to design new drug candidates targeting specific DNA methylation regions.