Adductome Explained

At its simplest, the adductome is the totality of chemical adducts that are present in particular cellular macromolecules such as DNA, and RNA, or proteins found within the organism.^[1] These adducts can detrimentally alter the chemical properties of these macromolecules and are therefore also referred to as damage. Adducts may arise as a consequence of the chemical reaction between a given "physicochemical agent to which an organism is exposed across the lifespan" (sometimes referred to as the exposome). These physicochemical agents can be exogenous in origin, and include ionizing and non-ionizing radiation, the diet, lifestyle factors, pollution, and xenobiotics. They made damage the macromolecules directly, or indirectly e.g., some xenobiotic substances require metabolism of the xenobiotic to produce a chemically reactive metabolite which can then form a covalent bond with the endogenous macromolecule. Agents that damage macromolecules can also arise from endogenous sources, such as reactive oxygen species that are a side product of normal respiration, leading to the formation of oxidatively damaged DNA^[2] etc., or other reactive species e.g., reactive nitrogen, sulphur, carbon, selenium and halogen species.^[3]

The term "adductome" first appeared in a journal article in 2005.^[4] Although originally the term related to adducts of DNA, the adductomic approach has now been adopted by protein chemists in their attempts to identify protein adducts. More recently, this has been extended by Kanaly's group to include RNA adducts.^[5] Most recently, nucleic acid adductomics has been reported, which has to potential to study a range of DNA and RNA adducts.^[6]

DNA and RNA

DNA adducts arise from compounds that bind to DNA, that covalently modify the DNA, resulting in damage. This damage can result in mutations. These mutations can result in a variety of adverse health effects, including cancer and birth defects in multicellular organisms. The science of adductomics seeks to identify and measure all DNA, RNA or protein adducts, identify their origins, and determine their role in health and disease.

Cellular DNA and/or RNA adductomics is performed after the target nucleic acid has been extracted from the cells ^[7] (e.g., from cultured cells, or tissues). Urinary DNA adductomics non-invasively evaluates DNA adducts that are present in urine,^[8] following their DNA repair.^[9]

Nucleic acid

Nucleic acid (NA) adductomics brings together DNA-, RNA- and, to some extent, protein adductomics to provide a more comprehensive view of the adduct burden to these molecules. NA adductomics builds upon previous DNA adductomics and DNA crosslinkomics ^[10] (which aims to analyze the totality of DNA-DNA crosslinks ^[11]) assays ^[12] and encompasses the analysis of modified (2′-deoxy)ribonucleosides (2′-dN/rN), modified nucleobases (nB), plus: DNA-DNA, RNA-RNA, DNA-RNA, DNA-protein, and RNA-protein crosslinks. Interestingly, many of these types of adducts are seen in urine from healthy humans, using urinary NA adductomics. Confirmation of the presence of DNA-RNA crosslinks in urine came from a recent study that demonstrated the presence of cellular DNA-RNA crosslinks, arising from formaldehyde exposure.^[13]

Notes and References

1. Rappaport SM, Li H, Grigoryan H, Funk WE, Williams ER . Adductomics: characterizing exposures to reactive electrophiles . Toxicology Letters . 213 . 1 . 83–90 . August 2012 . 21501670 . 4758449 . 10.1016/j.toxlet.2011.04.002 . We define an ‘adductome’ as the totality of such adducts with a given nucleophilic target. .
2. Cooke MS, Evans MD, Dizdaroglu M, Lunec J . Oxidative DNA damage: mechanisms, mutation, and disease . FASEB Journal . 17 . 10 . 1195–1214 . July 2003 . 12832285 . 10.1096/fj.02-0752rev . free . 1132537 .
3. Sies H, Belousov VV, Chandel NS, Davies MJ, Jones DP, Mann GE, Murphy MP, Yamamoto M, Winterbourn C . 6 . Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology . Nature Reviews. Molecular Cell Biology . 23 . 7 . 499–515 . July 2022 . 35190722 . 10.1038/s41580-022-00456-z . 247024086 .
4. Tomonari M, Kanaly RA, Tomoyuki H, Haruhiko S, Hirokazu T, Saber M . 2005 . DNA adductome strategy for detection of multiple DNA adducts. . Nippon Kankyo Hen'igen Gakkai Taikai Puroguramu . Yoshishu . 34 . 77 . Program of the Annual Meeting of the Japanese Society of Mutagenesis .
5. Takeshita T, Kanaly RA . In vitro DNA/RNA Adductomics to Confirm DNA Damage Caused by Benzo[''a'']pyrene in the Hep G2 Cell Line . Frontiers in Chemistry . 7 . 491 . 2019 . 31338364 . 10.3389/fchem.2019.00491 . 6629907 . 2019FrCh....7..491T . free .
6. Cooke MS, Chang YJ, Chen YR, Hu CW, Chao MR . Nucleic acid adductomics - The next generation of adductomics towards assessing environmental health risks . The Science of the Total Environment . 856 . Pt 2 . 159192 . January 2023 . 36195140 . 10.1016/j.scitotenv.2022.159192 . 2023ScTEn.856o9192C . 263480149 .
7. Balbo S, Turesky RJ, Villalta PW . DNA adductomics . Chemical Research in Toxicology . 27 . 3 . 356–366 . March 2014 . 24437709 . 3997222 . 10.1021/tx4004352 .
8. Cooke MS, Hu CW, Chang YJ, Chao MR . Urinary DNA adductomics - A novel approach for exposomics . Environment International . 121 . Pt 2 . 1033–1038 . December 2018 . 30392940 . 10.1016/j.envint.2018.10.041 . 6279464 . 2018EnInt.121.1033C .
9. Evans MD, Saparbaev M, Cooke MS . DNA repair and the origins of urinary oxidized 2'-deoxyribonucleosides . Mutagenesis . 25 . 5 . 433–442 . September 2010 . 20522520 . 10.1093/mutage/geq031 . free .
10. Hu CW, Chang YJ, Cooke MS, Chao MR . DNA Crosslinkomics: A Tool for the Comprehensive Assessment of Interstrand Crosslinks Using High Resolution Mass Spectrometry . Analytical Chemistry . 91 . 23 . 15193–15203 . December 2019 . 31670503 . 6891145 . 10.1021/acs.analchem.9b04068 .
11. Noll DM, Mason TM, Miller PS . Formation and repair of interstrand cross-links in DNA . Chemical Reviews . 106 . 2 . 277–301 . February 2006 . 16464006 . 2505341 . 10.1021/cr040478b .
12. Stornetta A, Villalta PW, Hecht SS, Sturla SJ, Balbo S . Screening for DNA Alkylation Mono and Cross-Linked Adducts with a Comprehensive LC-MS(3) Adductomic Approach . Analytical Chemistry . 87 . 23 . 11706–11713 . December 2015 . 26509677 . 5126974 . 10.1021/acs.analchem.5b02759 .
13. Dator RP, Murray KJ, Luedtke MW, Jacobs FC, Kassie F, Nguyen HD, Villalta PW, Balbo S . 6 . Identification of Formaldehyde-Induced DNA-RNA Cross-Links in the A/J Mouse Lung Tumorigenesis Model . Chemical Research in Toxicology . 35 . 11 . 2025–2036 . November 2022 . 36356054 . 10336729 . 10.1021/acs.chemrestox.2c00206 .