Etheno Adducts of Nucleic Acids and their Carcinogenic Aspects

Saptaparna Dasgupta, Bennett University

Nucleic acids have been known to be the fundamental molecules for passing on genetic information from the parents to offspring since 1944. The recent discovery of etheno adducts of nucleic acids has opened up to new dimensions in the field of biochemical studies. Etheno adducts of nucleic acids have a 5-membered ring attached to adenosine, cytosine, and guanosine, thereafter, leading to the synthesis of ATP analogues. It can also be derived from vinyl monomers, which are in turn responsible for base mutation and therefore cancer. Also, endogenous etheno DNA adducts were derived from reacting bis-electrophiles, formed via lipid peroxidation. In cases of mispairing of the etheno adducts either in free-form oligonucleotides or within the active sites of DNA polymerase, they are repaired by certain specific enzymes.

Characterization of Wyosine in tRNA

In the tRNA, the Y base such as wyosine, derived from 1,N 2-ꜫ-Guo, are found only in the tRNA of animals, yeasts, and archaebacteria. Wyosine is found at the 37th position of the phenylalanine residue, specific to the tRNA at the 3’ end (in Fig). Biosynthesis of the etheno compounds, such as wyosine and its derivatives involve complex pathways, and the overall process turns out to be expensive. It involves the utilization of keto enols, hydroperoxide, and epoxides as substrates in the reaction. The etheno adducts having branched structures are depicted to produce mutations and mis-insertions in cells.

Generation of Etheno Adducts through Vinyl Monomer

Vinyl chloride, being a potent carcinogen, was used to produce oncogenic tumours in rats. The oxidation reaction of free Ado and the produced 2-chloroethylene oxide from cytochrome P₄₅₀. This aided the formation of 1,N 6-ꜫ-Ado, and various other derivatives when exposed under the same conditions. 2-chloroethylene, produced as a product along with its similar structures react with nucleic acids and aid the formation of etheno adducts of nucleic acids. Certain other potential carcinogens resulted in the formation of etheno adducts of nucleic acids via the production of bis-electrophiles. The nitrogen groups in the nucleic acids which generate nitrosamines can also form etheno adducts. It follows the reaction of nucleophilic attack and is relevant for research studies on lipid peroxidation. The enzyme P₄₅₀ 2E1 was demonstrated to oxidize vinyl chloride and other potent carcinogens, targeting the Ado group. Thus, it is a potent catalyst in the oxidation of carcinogenic substances, such as vinyl monomers.

Generation of Etheno Adducts through Chemical Mechanism

The reaction with bis-electrophile involves two sites of reaction with a nucleophile; in conjunction, instability issues can also rise and generate electrophiles. Studies show that vinyl chloride and its derivatives were successful in reducing the radioactivity in microsomal Incubations. This indicates the presence of 2-haloethylene oxides instead of haloacetaldehydes. The reaction rate was observed to be higher for alcohol dehydrogenase as compared to epoxy hydrolase for the formation of etheno adducts.

Restoration of the Etheno Adducts

It is studied that different adducts have different half-lives based on the research conducted. In E. coli, the uracil DNA glycosylase, specific mismatch, and the alkyl purine DNA-N-glycosylase in humans are known to consume 1,N2-ꜫ-dGuo. The restoration of the etheno adducts of DNA can also be carried out through base excision repair (BER), nucleotide excision repair (NER), and AlkB repair. The BER repair involves the formation of an AP site on the etheno DNA. AlkB is known to catalyze hydroxylation and removes the alkyl group at the nitrogen bases (in Fig 2).

Thus, the etheno adduct of nucleic acid has a great impact in the field of biochemistry, biomedical science, and its applications. Based on the structure of tRNA it was possible for the discovery of the novel etheno adduction of nucleic acids. The contribution of vinyl monomers as carcinogens helped in the extensive research following both exogenous and endogenous sources, on cancer studies. All hail to the discovery of these etheno adducts and having an aimed future of induction of mutations in DNA.

Also read: Exosomes predicted to carry out protein secretion

Sources:

1. Guengerich, F.P., Ghodke, P.P. Etheno adducts: from tRNA modifications to DNA adducts and back to miscoding ribonucleotides. Genes and Environ 43, 24 (2021). https://doi.org/10.1186/s41021-021-00199-x
2. de Crécy-Lagard, V., Brochier-Armanet, C., Urbonavicius, J., Fernandez, B., Phillips, G., Lyons, B., Noma, A., Alvarez, S., Droogmans, L., Armengaud, J., & Grosjean, H. (2010). Biosynthesis of wyosine derivatives in tRNA: an ancient and highly diverse pathway in Archaea. Molecular biology and evolution, 27(9), 2062–2077. https://doi.org/10.1093/molbev/msq096

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About Author:

Saptaparna Dasgupta, currently a B. Tech 3rd year student, pursuing Biotechnology, is a diligent student and determined in terms of her career goals. Being a budding biotechnologist, she is open to all research fields of her course and passionate about knowledge. She is focused and constantly tries to improve her writing skills, also a project enthusiast and is fond of gaining hands-on experience in laboratories. She believes that all hard works and efforts pay off eventually and follows this as the motto of her life.