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. 2010 Dec 20;2010:709521.
doi: 10.4061/2010/709521.

Formation and Repair of Tobacco Carcinogen-Derived Bulky DNA Adducts

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Free PMC article

Formation and Repair of Tobacco Carcinogen-Derived Bulky DNA Adducts

Bo Hang. J Nucleic Acids. .
Free PMC article

Abstract

DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N-nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O(6)-alkylguanine DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects.

Figures

Figure 1
Figure 1
Schematic presentation of the formation, repair and mutagenic potential of tobacco carcinogen-induced bulky adducts in genomic DNA. The formation of a bulky DNA adduct (marked in red), if not repaired or poorly repaired, results in multiple genetic changes such as cell death and gene mutation. TLS (translesion DNA synthesis) can prevent a mutation by error-free incorporation opposite the adduct. Error-prone incorporation at the adduct site by replicative or translesional DNA pols is the source for mutation. Only those adducts that finally escape all the defense mechanisms may lead to biologically important mutations.
Figure 2
Figure 2
Structures of tobacco carcinogens, metabolites, and bulky dG adducts. These are only the partial list of DNA reactive carcinogens in cigarette smoke. The dG adducts listed are representatives of the adducts formed by the corresponding metabolites. Note that the stereochemistry of BPDE-DNA adducts is complex (see text). Acrolein can form two propano dG isomers, γ-HO-PdG (major), and α-HO-PdG (minor). CAA forms angular N2,3-εG, an isomer for 1, N2-εG.
Figure 3
Figure 3
Structures of smoking-induced bulky DNA adducts that are substrates for NER.
Figure 4
Figure 4
Multiple benzene metabolites, different types of DNA lesions, and proposed biological effects. Benzene has a complex metabolism and the listed metabolites are not a complete list. The adducts formed include those identified in vitro and in vivo, stable and unstable, bulky and oxidized adducts. DSBs are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. Repair of benzene-DNA adducts may include multiple mechanisms such as BER, NER, and NIR. Only those adducts that finally escape all the defense mechanisms such as repair, or are misrepaired, may lead to mutations. Persistence or coexistence of different types of lesions could form a broad-based attack on the genomic stability. It is also known that a number of benzene metabolites can inhibit topoisomerase II (topo II) activity, which may represent a potential mechanism for benzene's clastogenic effects [326].
Figure 5
Figure 5
Structures of smoking-induced bulky DNA adducts that are substrates for BER.
Figure 6
Figure 6
Structures of smoking-induced bulky DNA adducts that are substrates for NIR.
Figure 7
Figure 7
Summary of specificity of repair of tobacco carcinogen-induced bulky DNA adducts by the major DNA repair pathways. Some of the nonbulky DNA lesions and their repair mechanisms are also presented. For example, DSBs caused by cigarette smoke are repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR). Note that overlapping substrate specificity is common.
Figure 8
Figure 8
Stable nicotine-derived secondary products after reacting with ozone (O3) or nitrous acid (HONO). All the structures illustrated were positively identified except for myosmine that was tentatively identified. HONO can be adsorbed from air source or derived from surface-catalyzed reaction. Adopted from the work by Destaillats et al. [317] and Sleiman et al. [241].

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