© Borgis - New Medicine 3/2012, s. 68-73
*Paweł Kowalczyk
The influence of exocyclic DNA adducts in bacterial and mammalian genome instability
Interdisciplinary Centre for Mathematical and Computational Modelling Warsaw University
Head of Department: prof. Marek Niezgódka, MD, PhD
Summary
Oxidative stress enhances lipid peroxidation (LPO) implicated in the promotion and progression of carcinogenesis. One of the major LPO products is trans-4-hydroxy-2-nonenal (HNE), may to react with guanosine and under peroxidizing conditions also with adenosine. Additionally the same effect may induce environmental carcinogens, e.g. vinyl chloride and its metabolite chloroacetaldehyde (CAA). These compounds CAA and HNE introduce promutagenic exocyclic etheno and propano adducts into DNA, among them 1,N2-propanodeoxyguanine (PdG), 1,N6-ethenoadenine (1,N6-εA), 3,N4-ethenocytosine (3,N4-εC), N2, 3-ethenoguanine (N2,3-εG) and 1,N2-ethenoguanine (1,N2-εG). CAA-induced additionally DNA damage in regions which revealed secondary structure perturbations rich in mutation hot-spots also in bacterial and mammalian genome. These perturbations may inhibited DNA synthesis and induced mechanisms of DNA repair such as BER or NER. Base excision repair constitutes the primary defense against lesions that do not heavily distort the DNA structure. BER is responsible for the removal of a variety of lesions. These include spontaneous hydrolytic depurination of DNA, deamination of bases, products of reaction with hydroxyl radicals, and covalent DNA adducts formed by intracellular LPO and small reactive metabolites, such as methylating agents. Repair is initiated by the action of a damage-specific DNA N-glycosylase that is responsible for the recognition and removal of an altered base through cleavage of the N-glycosylic bond and action of AP-endonuclease. Nucleotide excision repair (NER) is the most versatile and flexible DNA repair pathway of living cells as it deals with a wide range of structurally unrelated DNA lesions. NER corrects a wide array of DNA lesions that distort the DNA double helix, interfere in base pairing and block DNA duplication and transcription. The most common examples of these lesions are the cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4 PPs) induced by ultraviolet radiation (UV) and bases with large substitutes derived from chemicals such as polycyclic aromatic hydrocarbons or exocyclic adducts.
Formation of exocyclic DNA adducts
Cellular DNA is continuously exposed to a variety of agents that alter its structure. These agents are both endogenous and exogenous, and include normal cellular metabolism, cell injury, inflammation, ionizing radiation and chemical agents. Accumulating evidence indicates that water, oxygen and endogenous alkylation are the main contributors to overall DNA damage (1).
These agents bring a considerable threat to living cells. Although both prokaryotic and eukaryotic cells are equipped with diverse DNA repair systems (2), removal of DNA lesions in an error-free way sometimes is not efficient enough and damage escapes processing before replication. Unrepaired DNA damage leads to various biological consequences, such as mutations or cell death, and subsequently to carcinogenesis, aging, and degenerative diseases (3).
Exocyclic DNA adducts are produced by endogenous and exogenous agents. Of the exocyclic DNA adducts, etheno (ε) bases have been the most widely studied over the last 25 years, as they are is formed by many genotoxic carcinogens, e.g., vinyl chloride or chloroacetaldehyde (4) and are also produced endogenously in animals and man. This class of DNA lesions affects normal Watson-Crick base pairing in DNA and was shown to be mutagenic in E.coli and mammalian cells (4).
It has been estimated that chronic inflammation is involved in the development of about one-forth of all cancers worldwide. Inflammatory response leads to recruitment of activated leukocytes, which release high quantities of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Hydrogen peroxide can produce hydroxyl radicals in reaction with metal ions. Direct proof comes from the work of Dizdaroglu (5) who showed that exposure of human cells to activated leukocytes causes DNA base modifications typical of hydroxyl radical attack. ROS also interact with membrane lipids causing their fragmentation and production of reactive aldehydes, which are able to interact with nucleic acids and form exocyclic DNA adducts. Etheno bases were first described by Kochetkov (6), who identified them as fluorescent analogues for biochemical studies and probes for nucleic acid structures although, among different exocyclic adducts only 1,N6 – ethenoadenine possesses fluorescent properties. The renewed interest in exocyclic DNA lesions in the 1990s was due to the development of ultrasensitive detection methods notably for etheno- and propano-DNA adducts which made it possible to study the formation of exocyclic adducts in experimental animals and humans. In 1994, unequivocal identification of the malondialdehyde-derived deoxyguanosine (M1-dG) adduct was reported by Chaudhary (7) in human liver. The same adduct was later also found in human breast and leukocytes. In 1995, Swenberg and co-workers found background levels of etheno- and propano-adducts in DNA of various human and rodent tissues and confirmed the presence of N2, 3-εdG in human liver by mass spectrometric techniques. These findings suggested an endogenous pathway (fig. 1) for the formation of exocyclic adducts via lipid peroxidation products.
Fig.1. Proposed scheme of carcinogenic factor leading to oxidative stress-induced reactive oxygen species (ROS) and nitrogen (RNS) species; which cause exocyclic DNA-base damage. Where iNOS; inducible nitric oxide synthase (7).
Oxidative stress and lipid peroxidation
Chronic inflammatory infection is one of the sources of free oxygen radicals and also leads to nitric oxide synthase (NOS) induction and therefore to NO synthesis. Oxidative stress processes enhance the generation of such reactive oxygen species as O2, H2O2 and OH.
The most reactive molecule is the hydroxyl radical. Its production can be increased in response to accumulation of free Cu and Fe ions in tissues (mainly in the liver) which is known to occur in some procancerogenic diseases, Wilson disease and primary hemochromatosis. These transient metal ions participate in Fenton and Haber-Weiss reactions to produce hydroxyl radicals:
Fe 2+ + H2O2 → •OH + OH– + Fe3+
O2•– + Fe3+ → O2 + Fe2+
and Haber Weiss reactions;
Fe2+/Fe3+
O2•– + H2O2 → OH• + OH– + O2
Poly-unsaturated lipids, components of lipids bilayers which surround various subcellular micro-environments, are one of the possible targets of free radical attack. The toxic effect of lipid peroxidation (LPO) is connected with the loss of cell membranes function and cell viability (9). Lipid peroxidation occurs in three steps; initiation, propagation and termination, and yields stable products which can either directly react with nucleic acids, or be further metabolized into more reactive compounds (tab. 1).
Table 1. Main carbonyl products of lipid peroxidation separated and stimulated by carbon tetrachloride or ADP-iron in isolated rat hepatocytes and rat liver microsomal suspensions (10).
| Polar carbonyls: |
Malondialdehyde
Acrolein
Crotonaldehyde |
| Non-polar carbonyls: |
Hydroxyalkenals:
4-hydroxy-2-hexenal
4-hydroxy-2-nonenal
4-hydroxy-2,5-dienal |
HNE – a major LPO product of divergent reactivity
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Piśmiennictwo
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