DNA Adduct Portal

Humans are continuously exposed to hazardous chemicals in the environment and diet, or to endogenously produced electrophiles, all of which can form covalent modifications to DNA (DNA adducts). If not repaired, these lesions can cause polymerase errors during DNA replication which can result in mutations. Critical DNA adducts that occur in cancer driver genes, such as H-ras and K-ras oncogenes and the p53 tumor suppressor gene, are thought to initiate chemical carcinogenesis in experimental animal models and cancers in humans.

The infographic shows how xenobiotics can lead to cancer. A normal cell is exposed to xenobiotics, undergoing either detoxication or bioactivation. Bioactivation can produce reactive metabolites which can react with DNA or protein producing DNA adducts or protein adducts, respectively. Protein adducts can lead to toxicity. DNA adducts can be repaired, but if not, can cause mutations leading to a cancer cell or cell death.

Reference: Yun, B-H. et. al. DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans. Mass Spec Rev. 2018, 1-28. PMID: 29889312

Project: "Development of a DNA Adduct Database"

Summary: The targeted analysis of DNA adducts over the past 30 years has revealed that the human genome contains a wide array of DNA adducts. With the advancement of high-resolution mass spectrometry instrumentation and new scanning technologies, untargeted “omics” approaches have become available to simultaneously screen for multiple DNA adducts in a single assay. However, the development of this emerging field of DNA adductomics is hindered by the lack of a publicly available mass spectral database for DNA adduct identification and characterization. Our goal is to develop and curate a comprehensive database of DNA adducts standards, obtained from international collaborators and commercial sources, to be freely available and searchable by the public. The database contains high-resolution MS2 and MS3 mass spectra of the adduct standards via Orbitrap MS and Q-TOF MS at various collision energies to characterize adduct structures. The successful establishment of a validated DNA adduct mass spectral database in a searchable, reference library is critical for the comprehensive analysis of DNA adductome profiles from cellular DNA, urine, and other biological matrices. This database will facilitate the usage of DNA adductomics in human cohort studies and advance our understanding of the relationships between external and internal exposures and disease risk.

References:

R03 Grant Application: Development of a DNA Adductome Database. R03ES031188
Guo, J. et. al. Development of a DNA adductome mass spectral database. Chem. Res. Toxicol. 2020, 33 (4), 852–854. PMID: 32223224
Walmsley, S.J et al. Mass Spectral Library for DNA Adducts. Chem. Res. Toxicol. 2024 37 (2), 302-310. PMID:38231175

MS data collection:

Orbitrap MS spectra: Drs. Jingshu Guo, Peter Villalta, Robert Turesky (Analytical Biochemistry Shared Resource, Masonic Cancer Center, University of Minnesota)
Q-TOF MS spectra: Drs. Anamary Tarifa, Anthony P. De Caprio (Forensic and Analytical Toxicology Facility, Florida International University), and Dr. Marcus S. Cooke (University of South Florida)

Database curation:

Dr. Scott J. Walmsley (University of Minnesota)
Mr. Abderrahman Day (University of Minnesota)

Website creation:

Dr. Jingshu Guo (University of Minnesota)
Dr. Peter Villalta (University of Minnesota)

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