Approximately 8.3% of the US population has diabetes, which is manifested by the development of microvascular pathology in the retina, renal glomerulus and peripheral nerve, rendering diabetes a leading cause of blindness, end-stage renal disease and various debilitating neuropathies. Colorectal cancer is the 3rd most common cancer in both men and women, and it accounts for ~9% of all cancer deaths. Thus, a better understanding about the etiology for the development of diabetic complications and gastrointestinal cancer may lead to better strategies for the prevention and treatment of these diseases, thereby saving lives and improving the quality of life for numerous patients suffering from these diseases. Hyperglycemia in diabetic patients and exposure to N-nitroso compounds in the gastrointestinal track can both give rise to carboxyalkylating agents that can modify DNA. The long-term goal of this project is to understand the human health consequences from exposure to these carboxyalkylating agents. We have made outstanding progress in the first funding cycle, where we have established in detail the carboxymethylation chemistry of DNA, synthesized oligodeoxyribonucleotides harboring site-specifically incorporated carboxymethylated DNA lesions, assessed the formation of the carboxyalkylated DNA lesions in mammalian cells, and investigated how these lesions compromised the efficiency and fidelity of DNA replication in vitro and in cells. In this competitive renewal, we will employ a multi-pronged and innovative approach to investigate how the carboxymethylated DNA lesions compromise the flow of genetic information by altering the efficiency and fidelity of DNA transcription, how the replicative bypass of the carboxyalkylated lesions is modulated by post-translational modifications of translesion synthesis DNA polymerases, and how exposure to carboxyalkylating agents leads to kinome reprogramming in human cells. The outcome of the proposed research will bring our understanding about the human health consequences from exposure to carboxyalkylating agents to a significant new level. In addition, the results of our proposed studies may ultimately lead to the development of new strategies for the prevention and treatment of diabetic complications and gastrointestinal cancers.

Public Health Relevance

Humans are exposed to byproducts of glycolysis and N-nitroso compounds in the gastrointestinal tract, which results in the carboxyalkylation of nucleobases in DNA. The proposed research will reveal the implications of hyperglycemia and exposure to N-nitroso compounds in the etiology of diabetic complications and gastrointestinal tumors. The outcome of the proposed research will ultimately lead to the discovery of novel risk factors for developing these pathological conditions and new targets for treating these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK082779-06
Application #
8775429
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jones, Teresa L Z
Project Start
2009-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Chemistry
Type
Earth Sciences/Resources
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92521
Dai, Xiaoxia; You, Changjun; Wang, Yinsheng (2016) The Functions of Serine 687 Phosphorylation of Human DNA Polymerase η in UV Damage Tolerance. Mol Cell Proteomics 15:1913-20
Yu, Yang; Wang, Jianshuang; Wang, Pengcheng et al. (2016) Quantification of Azaserine-Induced Carboxymethylated and Methylated DNA Lesions in Cells by Nanoflow Liquid Chromatography-Nanoelectrospray Ionization Tandem Mass Spectrometry Coupled with the Stable Isotope-Dilution Method. Anal Chem 88:8036-42
You, Changjun; Wang, Yinsheng (2016) Mass Spectrometry-Based Quantitative Strategies for Assessing the Biological Consequences and Repair of DNA Adducts. Acc Chem Res 49:205-13
You, Changjun; Wang, Pengcheng; Nay, Stephanie L et al. (2016) Roles of Aag, Alkbh2, and Alkbh3 in the Repair of Carboxymethylated and Ethylated Thymidine Lesions. ACS Chem Biol 11:1332-8
Miao, Weili; Xiao, Yongsheng; Guo, Lei et al. (2016) A High-Throughput Targeted Proteomic Approach for Comprehensive Profiling of Methylglyoxal-Induced Perturbations of the Human Kinome. Anal Chem 88:9773-9779
Liu, Shuo; Wang, Yinsheng (2015) Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts. Chem Soc Rev 44:7829-54
McIntyre, Justyna; McLenigan, Mary P; Frank, Ekaterina G et al. (2015) Posttranslational Regulation of Human DNA Polymerase ι. J Biol Chem 290:27332-44
You, Changjun; Wang, Jianshuang; Dai, Xiaoxia et al. (2015) Transcriptional inhibition and mutagenesis induced by N-nitroso compound-derived carboxymethylated thymidine adducts in DNA. Nucleic Acids Res 43:1012-8
You, Changjun; Wang, Yinsheng (2015) Quantitative measurement of transcriptional inhibition and mutagenesis induced by site-specifically incorporated DNA lesions in vitro and in vivo. Nat Protoc 10:1389-406
Xiao, Yongsheng; Guo, Lei; Wang, Yinsheng (2014) A targeted quantitative proteomics strategy for global kinome profiling of cancer cells and tissues. Mol Cell Proteomics 13:1065-75

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