Program Official

Principal Investigator

Yinsheng
Wang
Awardee Organization

University Of California Riverside
United States

Fiscal Year
2021
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

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

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 longlasting 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.

Publications

  • Tang F, Yuan J, Yuan BF, Wang Y. DNA-Protein Cross-Linking Sequencing for Genome-Wide Mapping of Thymidine Glycol. Journal of the American Chemical Society. 2022 Jan 12;144(1):454-462. Epub 2022 Jan 3. PMID: 34978433
  • Ma CJ, Li G, Shao WX, Min YH, Wang P, Ding JH, Xie NB, Wang M, Tang F, Feng YQ, Ci W, Wang Y, Yuan BF. Single-Nucleotide Resolution Mapping of N6-Methyladenine in Genomic DNA. ACS central science. 2023 Aug 28;9(9):1799-1809. doi: 10.1021/acscentsci.3c00481. eCollection 2023 Sep 27. PMID: 37780356
  • Miao W, Fan M, Huang M, Li JJ, Wang Y. Targeted Profiling of Heat Shock Proteome in Radioresistant Breast Cancer Cells. Chemical research in toxicology. 2019 Feb 18;32(2):326-332. Epub 2019 Jan 11. PMID: 30596229
  • Yu Y, Wang P, Cui Y, Wang Y. Chemical Analysis of DNA Damage. Analytical chemistry. 2018 Jan 2;90(1):556-576. Epub 2017 Nov 7. PMID: 29084424
  • Cai R, Bade D, Liu X, Huang M, Qi TF, Wang Y. Targeted Quantitative Profiling of GTP-Binding Proteins Associated with Metastasis of Melanoma Cells. Journal of proteome research. 2021 Nov 5;20(11):5189-5195. Epub 2021 Oct 25. PMID: 34694799
  • Tang F, Liu S, Li QY, Yuan J, Li L, Wang Y, Yuan BF, Feng YQ. Location analysis of 8-oxo-7,8-dihydroguanine in DNA by polymerase-mediated differential coding. Chemical science. 2019 Mar 11;10(15):4272-4281. doi: 10.1039/c8sc04946g. eCollection 2019 Apr 21. PMID: 31015952
  • Miao W, Guo L, Wang Y. Imatinib-Induced Changes in Protein Expression and ATP-Binding Affinities of Kinases in Chronic Myelocytic Leukemia Cells. Analytical chemistry. 2019 Mar 5;91(5):3209-3214. Epub 2019 Feb 20. PMID: 30773012
  • Bade D, Cai Q, Li L, Yu K, Dai X, Miao W, Wang Y. Modulation of N-terminal methyltransferase 1 by an N6-methyladenosine-based epitranscriptomic mechanism. Biochemical and biophysical research communications. 2021 Mar 26;546:54-58. Epub 2021 Feb 6. PMID: 33561748
  • Miao W, Li L, Wang Y. High-Throughput Targeted Quantitative Analysis of the Interaction between HSP90 and Kinases. Analytical chemistry. 2019 Sep 17;91(18):11507-11509. Epub 2019 Sep 4. PMID: 31476117
  • Liu X, Miao W, Huang M, Li L, Dai X, Wang Y. Elevated Hexokinase II Expression Confers Acquired Resistance to 4-Hydroxytamoxifen in Breast Cancer Cells. Molecular & cellular proteomics : MCP. 2019 Nov;18(11):2273-2284. Epub 2019 Sep 13. PMID: 31519767
  • Miao W, Yin J, Porter DF, Jiang X, Khavari PA, Wang Y. Targeted Proteomic Approaches for Proteome-Wide Characterizations of the AMP-Binding Capacities of Kinases. Journal of proteome research. 2022 Aug 5;21(8):2063-2070. Epub 2022 Jul 12. PMID: 35820187
  • Miao W, Li L, Wang Y. A Targeted Proteomic Approach for Heat Shock Proteins Reveals DNAJB4 as a Suppressor for Melanoma Metastasis. Analytical chemistry. 2018 Jun 5;90(11):6835-6842. Epub 2018 May 11. PMID: 29722524
  • Huang M, Wang Y. Roles of Small GTPases in Acquired Tamoxifen Resistance in MCF-7 Cells Revealed by Targeted, Quantitative Proteomic Analysis. Analytical chemistry. 2018 Dec 18;90(24):14551-14560. Epub 2018 Nov 30. PMID: 30431262
  • Huang M, Wang Y. Targeted Quantitative Proteomic Approach for Probing Altered Protein Expression of Small GTPases Associated with Colorectal Cancer Metastasis. Analytical chemistry. 2019 May 7;91(9):6233-6241. Epub 2019 Apr 12. PMID: 30943010
  • Ren W, Fan H, Grimm SA, Guo Y, Kim JJ, Yin J, Li L, Petell CJ, Tan XF, Zhang ZM, Coan JP, Gao L, Cai L, Detrick B, Çetin B, Cui Q, Strahl BD, Gozani O, Wang Y, Miller KM, O'Leary SE, Wade PA, Patel DJ, Wang GG, Song J. Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation. Proceedings of the National Academy of Sciences of the United States of America. 2020 Aug 4;117(31):18439-18447. Epub 2020 Jul 16. PMID: 32675241
  • Yang YY, Huang M, Wang Y. Targeted Proteomic Analysis of Small GTPases in Murine Adipogenesis. Analytical chemistry. 2020 May 5;92(9):6756-6763. Epub 2020 Apr 13. PMID: 32237738
  • Dong X, Sun J, Miao W, Chang CA, Wang Y. Proteome-Wide Characterizations of N6-Methyl-Adenosine Triphosphate- and N6-Furfuryl-Adenosine Triphosphate-Binding Capabilities of Kinases. Analytical chemistry. 2021 Oct 5;93(39):13251-13259. Epub 2021 Sep 22. PMID: 34549933
  • Miao W, Wang Y. Quantitative Interrogation of the Human Kinome Perturbed by Two BRAF Inhibitors. Journal of proteome research. 2019 Jun 7;18(6):2624-2631. Epub 2019 Apr 24. PMID: 30994353
  • Miao W, Yuan J, Li L, Wang Y. Parallel-Reaction-Monitoring-Based Proteome-Wide Profiling of Differential Kinase Protein Expression during Prostate Cancer Metastasis in Vitro. Analytical chemistry. 2019 Aug 6;91(15):9893-9900. Epub 2019 Jul 10. PMID: 31241916
  • Wang L, Lee JY, Gao L, Yin J, Duan Y, Jimenez LA, Adkins GB, Ren W, Li L, Fang J, Wang Y, Song J, Zhong W. A DNA aptamer for binding and inhibition of DNA methyltransferase 1. Nucleic acids research. 2019 Dec 16;47(22):11527-11537. PMID: 31733056
  • Li L, Miao W, Huang M, Williams P, Wang Y. Integrated Genomic and Proteomic Analyses Reveal Novel Mechanisms of the Methyltransferase SETD2 in Renal Cell Carcinoma Development. Molecular & cellular proteomics : MCP. 2019 Mar;18(3):437-447. Epub 2018 Nov 28. PMID: 30487242
  • Miao W, Li L, Wang Y. Identification of Helicase Proteins as Clients for HSP90. Analytical chemistry. 2018 Oct 16;90(20):11751-11755. Epub 2018 Sep 26. PMID: 30247883
  • Huang M, Qi TF, Li L, Zhang G, Wang Y. A Targeted Quantitative Proteomic Approach Assesses the Reprogramming of Small GTPases during Melanoma Metastasis. Cancer research. 2018 Sep 15;78(18):5431-5445. Epub 2018 Aug 2. PMID: 30072397
  • Liu X, Gonzalez G, Dai X, Miao W, Yuan J, Huang M, Bade D, Li L, Sun Y, Wang Y. Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m6A-Based Epitranscriptomic Mechanism. Molecular therapy : the journal of the American Society of Gene Therapy. 2020 Dec 2;28(12):2593-2604. Epub 2020 Sep 5. PMID: 32956623
  • Huang M, Wang Y. GLOBAL AND TARGETED PROFILING OF GTP-BINDING PROTEINS IN BIOLOGICAL SAMPLES BY MASS SPECTROMETRY. Mass spectrometry reviews. 2021 May;40(3):215-235. Epub 2020 Jun 10. PMID: 32519381
  • Guo C, Xie C, Chen Q, Cao X, Guo M, Zheng S, Wang Y. A novel malic acid-enhanced method for the analysis of 5-methyl-2'-deoxycytidine, 5-hydroxymethyl-2'-deoxycytidine, 5-methylcytidine and 5-hydroxymethylcytidine in human urine using hydrophilic interaction liquid chromatography-tandem mass spectrometry. Analytica chimica acta. 2018 Nov 30;1034:110-118. Epub 2018 Jul 3. PMID: 30193624
  • Cai R, Huang M, Wang Y. Targeted Quantitative Profiling of GTP-Binding Proteins in Cancer Cells Using Isotope-Coded GTP Probes. Analytical chemistry. 2018 Dec 18;90(24):14339-14346. Epub 2018 Nov 28. PMID: 30433760
  • Miao W, Yang YY, Wang Y. Quantitative Proteomic Analysis Revealed Broad Roles of N6-Methyladenosine in Heat Shock Response. Journal of proteome research. 2021 Jul 2;20(7):3611-3620. Epub 2021 May 27. PMID: 34043365
  • Qi TF, Guo L, Huang M, Li L, Miao W, Wang Y. Discovery of TBC1D7 as a Potential Driver for Melanoma Cell Invasion. Proteomics. 2020 Jul;20(14):e1900347. Epub 2020 Jul 2. PMID: 32510182
  • Weng PJ, Gao Y, Gregory MT, Wang P, Wang Y, Yang W. Bypassing a 8,5'-cyclo-2'-deoxyadenosine lesion by human DNA polymerase η at atomic resolution. Proceedings of the National Academy of Sciences of the United States of America. 2018 Oct 16;115(42):10660-10665. Epub 2018 Oct 1. PMID: 30275308
  • Miao W, Bade D, Wang Y. Targeted Proteomic Analysis Revealed Kinome Reprogramming during Acquisition of Radioresistance in Breast Cancer Cells. Journal of proteome research. 2021 May 7;20(5):2830-2838. Epub 2021 Mar 19. PMID: 33739118
  • Miao W, Wang Y. Targeted Quantitative Kinome Analysis Identifies PRPS2 as a Promoter for Colorectal Cancer Metastasis. Journal of proteome research. 2019 May 3;18(5):2279-2286. Epub 2019 Apr 2. PMID: 30908912
  • Cai R, Dong X, Yu K, He X, Liu X, Wang Y. Chemical Proteomic Profiling of the Interacting Proteins of Isoprenoid Pyrophosphates. Analytical chemistry. 2020 Jun 16;92(12):8031-8036. Epub 2020 May 27. PMID: 32420730
  • Du H, Wang P, Li L, Amato NJ, Wang Y. Cytotoxic and Mutagenic Properties of C1' and C3'-Epimeric Lesions of 2'-Deoxyribonucleosides in Human Cells. ACS chemical biology. 2019 Mar 15;14(3):478-485. Epub 2019 Feb 25. PMID: 30768892
  • Liu X, Yuan J, Zhang X, Li L, Dai X, Chen Q, Wang Y. ATF3 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an N6-Methyladenosine-Based Epitranscriptomic Mechanism. Chemical research in toxicology. 2021 Jul 19;34(7):1814-1821. Epub 2021 Jul 2. PMID: 34213887
  • Dong X, Gao L, Song J, Wang Y. Chemical Proteomic Profiling of Lysophosphatidic Acid-Binding Proteins. Analytical chemistry. 2019 Dec 17;91(24):15365-15369. Epub 2019 Nov 27. PMID: 31765128