Effect of the Spiroiminodihydantoin Lesion on DNA Helix Stability and Nucleosome

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DESCRIPTION (provided by applicant): Deoxyribonucleic acid (DNA) is the biological molecule within cells that is responsible for transmitting and storing genetic information. Unfortunately, DNA can become damaged, jeopardizing the integrity of this information that is vital for preserving health. Agents that damage DNA, known as reactive oxygen species (ROS), are produced in the normal course of cellular respiration as cells make energy by converting oxygen into water. They can also be introduced by outside sources such as ionizing radiation and certain transition metals. The experiments proposed here will focus on examining a specific type of DNA damage called DNA base oxidation, where the structure of the DNA base, responsible for storing genetic information, is altered. This particular type of DNA damage has been implicated in causing cellular aging, cancer, and neurological disorders like Alzheimer's disease and amyotrophic lateral sclerosis. The goal of this proposal is to investigate the effect of the spiroiminodihydantoin (Sp) lesion on the stability and structure of DNA. This highly-mutagenic lesion, which is formed when ROS react with guanine bases in DNA, produces the same types of mutations found in some human lung tumors. Differential scanning calorimetry (DSC) experiments will be undertaken in Specific Aims 1 & 2 to fully examine the thermodynamic stability of the two different isomeric forms of the Sp lesion in a variety of DNA sequences. The formation and packaging of Sp lesions in nucleosomes will be examined in Specific Aim 3 to investigate the impact of this lesion on eukaryotic cells. The results from these studies will provide important insight into how the biological processing of the Sp lesion in cells contributes to causing diseases like cancer. PUBLIC HEALTH RELEVANCE: Oxidative DNA damage can cause cellular aging, cancer, and neurological disorders. The goal of this proposal is to investigate the effect of a particular type of this damage, known as the spiroiminodihydantoin (Sp) lesion, on the stability and structure of DNA. The results from these studies will provide important insight into how the biological processing of the Sp lesion contributes to causing disease.