Identification of Formaldehyde-Induced DNA–RNA Cross-Links in the A/J Mouse Lung Tumorigenesis ModelClick to copy article linkArticle link copied!
- Romel P. DatorRomel P. DatorMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Romel P. Dator
- Kevin J. MurrayKevin J. MurrayDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, St. Paul, Minnesota 55108, United StatesCenter for Mass Spectrometry and Proteomics, University of Minnesota, St. Paul, Minnesota 55108, United StatesMore by Kevin J. Murray
- Matthew W. LuedtkeMatthew W. LuedtkeMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Matthew W. Luedtke
- Foster C. JacobsFoster C. JacobsMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesDivision of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Foster C. Jacobs
- Fekadu KassieFekadu KassieMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108, United StatesMore by Fekadu Kassie
- Hai Dang NguyenHai Dang NguyenMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesDepartment of Pharmacology, College of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Hai Dang Nguyen
- Peter W. VillaltaPeter W. VillaltaMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesDepartment of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Peter W. Villalta
- Silvia Balbo*Silvia Balbo*Email: [email protected]. Phone: (612) 624-4240. Fax: (612) 624-3869.Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United StatesDivision of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, United StatesMore by Silvia Balbo
Abstract
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in tobacco products, and exposure to it is likely one of the factors contributing to the development of lung cancer in cigarette smokers. To exert its carcinogenic effects, NNK must be metabolically activated into highly reactive species generating a wide spectrum of DNA damage. We have identified a new class of DNA adducts, DNA–RNA cross-links found for the first time in NNK-treated mice lung DNA using our improved high-resolution accurate mass segmented full scan data-dependent neutral loss MS3 screening strategy. The levels of these DNA–RNA cross-links were found to be significantly higher in NNK-treated mice compared to the corresponding controls, which is consistent with higher levels of formaldehyde due to NNK metabolism as compared to endogenous levels. We hypothesize that this DNA–RNA cross-linking occurs through reaction with NNK-generated formaldehyde and speculate that this phenomenon has broad implications for NNK-induced carcinogenesis. The structures of these cross-links were characterized using high-resolution LC–MS2 and LC–MS3 accurate mass spectral analysis and comparison to a newly synthesized standard. Taken together, our data demonstrate a previously unknown link between DNA–RNA cross-link adducts and NNK and provide a unique opportunity to further investigate how these novel NNK-derived DNA–RNA cross-links contribute to carcinogenesis in the future.
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This article is cited by 5 publications.
- Scott J. Walmsley, Jingshu Guo, Anamary Tarifa, Anthony P. DeCaprio, Marcus S. Cooke, Robert J. Turesky, Peter W. Villalta. Mass Spectral Library for DNA Adductomics. Chemical Research in Toxicology 2024, 37
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, 340-360. https://doi.org/10.1021/acs.chemrestox.3c00333
- Chiung-Wen Hu, Yuan-Jhe Chang, Wei-Hung Chang, Marcus S. Cooke, Yet-Ran Chen, Mu-Rong Chao. A Novel Adductomics Workflow Incorporating FeatureHunter Software: Rapid Detection of Nucleic Acid Modifications for Studying the Exposome. Environmental Science & Technology 2024, 58
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, 75-89. https://doi.org/10.1021/acs.est.3c04674
- Kevin J. Murray, Peter W. Villalta, Timothy J. Griffin, Silvia Balbo. Discovery of Modified Metabolites, Secondary Metabolites, and Xenobiotics by Structure-Oriented LC–MS/MS. Chemical Research in Toxicology 2023, 36
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, 1666-1682. https://doi.org/10.1021/acs.chemrestox.3c00209
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