The Influence of Exocyclic Dna Adducts in Bacterial and Mammalian Genome Instability

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.