This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A large number of studies have strongly implicated lipid peroxidation as a significant factor in the development of human cancers. Continuous production of reactive carbonyl compounds by the lipid peroxidation process can also contribute to age-dependent increases in mutations and cancer incidence. The nature of the DNA damage responsible for the mutagenic and cancer-promoting effects of lipid peroxidation products is currently not well understood. We have found that activation of lipid peroxidation in cultured human cells or rat liver in vivo led to extensive formation of DNA crosslinks with major histone proteins. Some of the crosslinks were determined to be mutagenic in human cells. These findings allowed us to propose the hypothesis that DNA-histone crosslinks represent a major class of mutagenic and genotoxic DNA lesions formed by lipid peroxidation in human cells. To determine the biological significance of DNA-histone crosslinks, we propose a series of studies that will examine (1) stress signaling responses activated by these lesions, (2) mutagenic and genotoxic properties of individual DNA-histone crosslinks and their repair intermediates, and (3) the role of major lipid peroxidation products in DNA-protein crosslinking. The results of the proposed studies will help elucidate molecular mechanisms of genetic damage by lipid peroxidation and contribute to a better understanding of the nature of the endogenous DNA damage. Establishment of the biological significance of DNA-histone crosslinks would provide the basis for their use as molecular biomarkers in the evaluation of dietary factors and chemopreventive agents in the amelioration of lipid peroxidation-dependent DNA damage.
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