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

用于评估 DNA 加合物的发生和修复的定量加合物组学方法

• 批准号: 10172860
• 负责人: Yinsheng Wang
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172860
• 关键词: Acetylcysteine; Affect; Cancer Biology; Coupled; Cultured Cells; Cytosine; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA biosynthesis; DNA lesion; DNA photoproducts; Development; Dilution Techniques; Environmental Exposure; Enzymes; Epigenetic Process; Etiology; Excision; Exposure to; Family; Gene Expression Regulation; Genetic Fingerprintings; Genetic Transcription; Human; Induced Mutation; Lead; Left; Lipid Peroxidation; Malignant Neoplasms; Mammalian Cell; Measurement; Mediating; Metabolism; Methods; Methylation; Modification; Molecular; Mus; Mutagens; Outcome; Play; Positioning Attribute; Prevention; Preventive; Process; Publishing; Reactive Oxygen Species; Research; Risk Factors; Role; Skin; Skin Cancer; Skin Tissue; Source; Specimen; Sunscreen Effect; Sunscreening Agents; Therapeutic; Tissues; Topical application; UV induced; Ultraviolet Rays; Veins; analytical method; animal tissue; base; cancer chemoprevention; cancer initiation; cancer prevention; cancer risk; cancer therapy; epigenetic regulation; genetic information; genetic manipulation; human disease; melanoma; methyl group; novel; oxidation; repaired; skin cancer prevention; stable isotope; sunlight-induced; ultraviolet irradiation

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.

该应用的长期目标是发现并表征基于加合组学的暴露 癌症风险评估和癌症预防的指标。内源性代谢和 环境暴露都会引起 DNA 损伤。如果不修复，产生的 DNA 加合物可能 通过抑制 DNA 复制和转录以及诱导突变来损害遗传信息的流动 在这些过程中。此外，哺乳动物细胞和组织中积累的 DNA 加合物的最终水平 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，用于定量测量各种相关的 DNA 加合物 癌症和其他人类疾病发展的病因学。这种方法也将使 DNA 加合物修复的特征，可能导致癌症发生的危险因素的发现 和开发，并指导有效癌症化学预防方法的开发。在这个 应用程序，我们建议通过采用和扩展我们最近的研究来建立 DNA 加合体方法 建立了 LC-MS/MS 方法，用于定量由活性氧、DNA 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，代表了 DNA 的一个重要子集 DNA加合物。然后我们将采用这种内合方法来研究 DNA 修复酶氧化诱导的 DNA 损伤和 DNA 表观遗传标记的水平，用于评估 DNA 加合物在黑色素瘤发展病因学中的意义，以及评估 防晒成分改变紫外线诱导的 DNA 加合物形成。拟议的研究将具有长期 通过提供简便的内合体平台对 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形成的危险因素和治疗/预防方法 去除DNA加合物。

项目成果

GLOBAL AND TARGETED PROFILING OF GTP-BINDING PROTEINS IN BIOLOGICAL SAMPLES BY MASS SPECTROMETRY.

• DOI: 10.1002/mas.21637
• 发表时间: 2021-05
• 期刊: Mass spectrometry reviews
• 影响因子: 6.6
• 作者: Huang M;Wang Y
• 通讯作者: Wang Y

Targeted Proteomic Approaches for Proteome-Wide Characterizations of the AMP-Binding Capacities of Kinases.

• DOI: 10.1021/acs.jproteome.2c00225
• 发表时间: 2022-08-05
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Miao, Weili;Yin, Jiekai;Porter, Douglas F.;Jiang, Xiaogang;Khavari, Paul A.;Wang, Yinsheng
• 通讯作者: Wang, Yinsheng

Targeted Proteomic Analysis Revealed Kinome Reprogramming during Acquisition of Radioresistance in Breast Cancer Cells.

靶向蛋白质组学分析表明，在乳腺癌细胞中采集放射线抗性期间的Kinome重编程。

• DOI: 10.1021/acs.jproteome.1c00075
• 发表时间: 2021-05-07
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Miao W;Bade D;Wang Y
• 通讯作者: Wang Y

Bypassing a 8,5'-cyclo-2'-deoxyadenosine lesion by human DNA polymerase η at atomic resolution.

人类 DNA 聚合酶 γ 在原子分辨率下绕过 8,5-环-2-脱氧腺苷损伤。

• DOI: 10.1073/pnas.1812856115
• 发表时间: 2018
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Weng,PeterJ;Gao,Yang;Gregory,MarkT;Wang,Pengcheng;Wang,Yinsheng;Yang,Wei
• 通讯作者: Yang,Wei

Chemical Proteomic Profiling of the Interacting Proteins of Isoprenoid Pyrophosphates.

• DOI: 10.1021/acs.analchem.0c01676
• 发表时间: 2020-05
• 期刊: Analytical chemistry
• 影响因子: 7.4
• 作者: Rong Cai;Xuejiao Dong;Kailin Yu;Xiaomei He;Xiaochuan Liu;Yinsheng Wang