Guilbaud A, Ghanegolmohammadi F, Wang Y, Leng J, Kreymerman A, Gamboa Varela J, Garbern J, Elwell H, Cao F, Ricci-Blair EM, Liang C, Balamkundu S, Vidoudez C, DeMott MS, Bedi K, Margulies KB, Bennett DA, Palmer AA, Barkley-Levenson A, Lee RT, Dedon PC. 2023. Discovery adductomics provides a comprehensive portrait of tissue-, age- and sex-specific DNA modifications in rodents and humans. Nucleic acids research. 51(20):10829-10845. Pubmed: 37843128 DOI:10.1093/nar/gkad822


DNA damage causes genomic instability underlying many diseases, with traditional analytical approaches providing minimal insight into the spectrum of DNA lesions in vivo. Here we used untargeted chromatography-coupled tandem mass spectrometry-based adductomics (LC-MS/MS) to begin to define the landscape of DNA modifications in rat and human tissues. A basis set of 114 putative DNA adducts was identified in heart, liver, brain, and kidney in 1-26-month-old rats and 111 in human heart and brain by 'stepped MRM' LC-MS/MS. Subsequent targeted analysis of these species revealed species-, tissue-, age- and sex-biases. Structural characterization of 10 selected adductomic signals as known DNA modifications validated the method and established confidence in the DNA origins of the signals. Along with strong tissue biases, we observed significant age-dependence for 36 adducts, including N2-CMdG, 5-HMdC and 8-Oxo-dG in rats and 1,N6-ϵdA in human heart, as well as sex biases for 67 adducts in rat tissues. These results demonstrate the potential of adductomics for discovering the true spectrum of disease-driving DNA adducts. Our dataset of 114 putative adducts serves as a resource for characterizing dozens of new forms of DNA damage, defining mechanisms of their formation and repair, and developing them as biomarkers of aging and disease.
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

Related Faculty

Photo of Rich Lee

Rich Lee seeks to understand heart failure and metabolic diseases that accompany human aging, and translate that understanding into therapies. Lee is an active clinician, regularly treating patients at Brigham and Women’s Hospital.

Search Menu