Insights into how the structural features of DNA adducts dictate local helical conformation and repairability: a computational study

Abstract

DNA damage occurs regularly and results in various biological consequences, including cancer. One specific type of DNA damage is the formation of adducts, which arise from various sources, including cigarette smoke and pesticides. The local helical structure of adducted DNA is dictated by the chemical composition of the lesion. Furthermore, various known conformations of adducted DNA have been shown to differentially impact DNA repair and replication. Although this underscores how the lesion dictates biological outcomes, structure–function relationships have yet to be fully explored. Thus, this thesis uses computational modelling to examine the complex interplay between the adduct chemical composition (e.g., bulky moiety shape, adduct linker type, and lesion number) and the resulting damaged DNA structure and lesion mutagenicity. Overall, novel trends in the helical conformation and lesion repairability as a function of the chemical structure of the DNA adduct are uncovered, which have implications in the severity of the long-term biological consequences.