The long-term objective of this application is to discover and characterize the adductomics-based exposure indicators for the assessment of cancer risks and for cancer prevention. Endogenous metabolism and environmental exposure can both give rise to DNA damage. If left unrepaired, the resulting DNA adducts may compromise the flow of genetic information by inhibiting DNA replication and transcription and inducing mutations in these processes. In addition, the ultimate levels of DNA adducts accumulated in mammalian cells and tissues are the result of a dynamic interplay between DNA adduct formation and repair. Thus, it is important to establish a robust analytical method for the quantitative measurement of a broad range of DNA adducts that are implicated in the etiology for the development of cancer and other human diseases. Such a method will also enable the characterizations of the repair of DNA adducts, which may lead to the discovery of risk factors for cancer initiation and development, and guide the development of approaches for effective cancer chemoprevention. In this application, we propose to establish a DNA adductomic approach by employing and expanding our recently established LC-MS/MS methods for the quantification of DNA adducts induced by reactive oxygen species, DNA photoproducts arising from UV irradiation, and DNA epigenetic marks, which represent a substantial subset of the DNA adductome. We will then employ this adductomic approach for investigating the modulations of the levels of oxidatively induced DNA lesions and DNA epigenetic marks by DNA repair enzymes, for assessing the implications of DNA adducts in the etiology of melanoma development, and for evaluating the effects of sunscreen components on altering UV-induced DNA adduct formation. The proposed research will have a long- lasting impact on the fields of DNA damage repair and cancer biology by offering a facile adductomic platform for characterizing the risk factors and therapeutic/preventive approaches that modulate the formation and removal of DNA adducts.
Humans are constantly exposed to endogenous and exogenous sources of DNA damage agents, and the resulting DNA adducts have been implicated in the initiation and development of cancer and other human diseases. The emphasis of the research proposed in this application is placed on developing a comprehensive and robust method for the quantitative profiling of DNA adducts in mammalian cells and tissues. The outcome of the proposed research may lead to the discovery of novel risk factors for cancer development and effective approaches for cancer prevention.