Etheno adducts: from tRNA modifications to DNA adducts and back to miscoding ribonucleotides

F Peter Guengerich,Pratibha P Ghodke

doi:10.1186/s41021-021-00199-x

Abstract

Etheno (and ethano) derivatives of nucleic acid bases have an extra 5-membered ring attached. These were first noted as wyosine bases in tRNAs. Some were fluorescent, and the development of etheno derivatives of adenosine, cytosine, and guanosine led to the synthesis of fluorescent analogs of ATP, NAD+, and other cofactors for use in biochemical studies. Early studies with the carcinogen vinyl chloride revealed that these modified bases were being formed in DNA and RNA and might be responsible for mutations and cancer. The etheno bases are also derived from other carcinogenic vinyl monomers. Further work showed that endogenous etheno DNA adducts were present in animals and humans and are derived from lipid peroxidation. The chemical mechanisms of etheno adduct formation involve reactions with bis-electrophiles generated by cytochrome P450 enzymes or lipid peroxidation, which have been established in isotopic labeling studies. The mechanisms by which etheno DNA adducts miscode have been studied with several DNA polymerases, aided by the X-ray crystal structures of these polymerases in mispairing situations and in extension beyond mispairs. Repair of etheno DNA adduct damage is done primarily by glycosylases and also by the direct action of dioxygenases. Some human DNA polymerases (η, κ) can insert bases opposite etheno adducts in DNA and RNA, and the reverse transcriptase activity may be of relevance with the RNA etheno adducts. Further questions involve the extent that the etheno adducts contribute to human cancer.

Highlights

Etheno adducts are interesting for a number of reasons
The history continues through organic synthesis and use in bioorganic chemistry and their discovery as DNA adducts derived from work with chemical carcinogens
Laib and Bolt [28] reported that 1,N6-ε-Ado was formed in the incubation of vinyl chloride with rat liver microsomes, poly-Ado, and NADPH, and 1,N6-εdAdo and 3,N4-ε-dCyd were formed in vitro under similar conditions [29]. 1,N6-ε-dAdo, 1,N6-ε-Ado, 3, N4-ε-dCyd, and 3,N4-ε-Cyd were identified as DNA and RNA adducts in livers of rats treated with 14C-vinyl chloride [29, 30]

Summary

Introduction

Etheno adducts are interesting for a number of reasons. One of us was first introduced to these in the late 1970s, and both of us continue to work with these today. Etheno derivatives of cofactors In 1971 Kochetov et al [17] reported that the reaction of 2-chloroacetaldehyde with 9-methyladenine and 1methylcytosine yielded the N-methyl derivatives of 1,N6ε-Ado and 3,N4-ε-Cyd (Fig. 1). Leonard and his associates used 2-chloroacetaldehyde to prepare 1,N6-εAdo and N3,4-ε-Cyd under mildly acidic conditions [18]. 1,N6-ε-dAdo, 1,N6-ε-Ado, 3, N4-ε-dCyd, and 3,N4-ε-Cyd were identified as DNA and RNA adducts in livers of rats treated with 14C-vinyl chloride [29, 30]. Kúsmierek and Singer [32] reported that 1,N2-ε-dGuo was formed in polynucleotides and DNA treated with 2-chloroacetaldehyde Both 2-choroethylene oxide and its rearrangement product 2-chloroacetaldehyde are capable of reacting with nucleic acids to generate etheno adducts (Fig. 7, Table 1) [27]. Endogenous etheno DNA adducts In the course of developing sensitive assays for DNA adducts, the Swenberg laboratory reported that N2,3-ε-

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