MERIT Award Recipient: Lawrence J. Marnett, Ph.D.
The Chemistry and Biology of Endogenous DNA Damage
Cancer results from progressive irreversible changes in our genetic material (DNA) that ultimately leads the uncontrolled growth of tumor cells, increased invasiveness to surrounding tissue, and the ability to spread to other organs. A major cause of genetic mutations is chemical damage to DNA. Damaged DNA is not copied accurately so as a result mutations are introduced when the cell divides. DNA damage was once thought to result exclusively from exposure to environmental agents such as cigarette smoke, ultraviolet light, etc. Over the past twenty-five years, attention has shifted to DNA damage caused by chemicals that are generated endogenously in our body. Our group has focused on DNA damage that occurs during the process of inflammation. Inflammation is a beneficial process that seeks to destroy or limit the spread of invading pathogens (e.g., bacteria or viruses). However, chronic inflammation induces significant tissue damage and is a risk factor for many different cancers. Our laboratory has focused on a class of compounds generated during inflammation called bifunctional aldehydes. These compounds arise from oxidation of polyunsaturated fatty acids in cell membranes or from degradation of the deoxyribose backbone of DNA. Several important bifunctional aldehydes are malondialdehyde, 4-hydroxynonenal, 4-oxononenal, and base propenal. These compounds react with deoxyguanosine and deoxyadenosine residues in DNA and form adducts that block the hydrogen bonding face of these deoxynucleoside bases. We are exploring the mutations induced by these adducts and the pathways by which they are repaired. Since these adducts are produced in all individuals to varying extents, there is a strong possibility that they make a major contribution to the mutations that are responsible for human cancer. To test this possibility, we are developing methods for detecting the presence of these adducts in human genes. The ultimate goal of this research is to determine the factors that contribute to generating endogenous DNA damage, how individuals vary in their response to this damage, and the role it plays in human cancer.