Quantitative Adductomics Approaches for Assessing the Occurrence and Repair of DNA Adducts

这项应用的长期目标是发现和表征基于内收切除术的暴露 用于评估癌症风险和癌症预防的指标。内源性代谢和 环境暴露都会导致DNA损伤。如果不修复，产生的DNA加合物可能会 通过抑制DNA复制和转录并诱导突变来危害遗传信息流 在这些过程中。此外，在哺乳动物细胞和组织中积累的DNA加合物的终极水平 是DNA加合物形成和修复之间动态相互作用的结果。因此，重要的是建立 一种稳健的分析方法，用于定量测量所涉及的广泛的DNA加合物 在癌症和其他人类疾病的病因学上。这种方法还将使 DNA加合物修复的特征，这可能导致发现致癌的危险因素 和发展，并指导开发有效的癌症化学预防方法。在这 应用，我们建议通过利用和扩展我们最近的 建立了LC-MS/MS法定量测定活性氧诱导的DNA加合物 紫外线照射产生的光产物和DNA表观遗传标记，它们代表了 DNA加合物组。然后，我们将使用这种加减法来研究 氧化诱导的DNA损伤水平和DNA修复酶的DNA表观遗传标记，用于评估 DNA加合物在黑色素瘤发生的病因学中的意义，以及用于评估 防晒成分对紫外线诱导的DNA加合物形成的影响。拟议的研究将有很长的- 通过提供一个方便的内收手术平台，对DNA损伤修复和癌症生物学领域产生持久影响 用于描述调节形成和预防的危险因素和治疗/预防方法 DNA加合物的去除。

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.