Enzymology of repair of etheno-adducts.
Etheno(epsilon)-adducts such as 1,N(6)-ethenoadenine (epsilon A), 3,N(4)-ethenocytosine (epsilon C), N(2),3-ethenoguanine (N(2),3-epsilon G), and 1,N(2)-ethenoguanine (1,N(2)-epsilon G) are produced in cellular DNA by two independent pathways: (i) by reaction with oxidised metabolites of vinyl chloride, 2-chloroacetaldehyde and 2-chloroethylene oxide; (ii) by endogenous processes through the interaction of lipid peroxidation (LPO)-derived aldehydes and hydroxyalkenals. They have been found in DNA isolated from human and rodent tissues. However, the levels of adducts were significantly increased by cancer risk factors contributing to lipid peroxidation and oxidative stress. The highly mutagenic and genotoxic properties of epsilon-adducts have been established in vitro by analysing steady-state kinetics of primer extension assays and in vivo by site-specific mutagenesis in mammalian cells. Therefore, the repair processes eliminating exocyclic adducts from DNA should play a crucial role in maintaining the stability of genetic information. The epsilon-adducts are eliminated by the base excision repair (BER) pathway, with DNA glycosylases being the key enzymes of this pathway. They remove epsilon-adducts from DNA by hydrolysing the N-glycosidic bond between the damaged base and deoxyribose, leaving an abasic site in DNA. The ethenobase-DNA glycosylases have been identified and their enzymatic properties described. They are specific for a given epsilon-base although they can also excise different types of modified bases, such as alkylated purines, hypoxanthine and uracil. The fact that ethenoadducts are recognised and excised with high efficiency by various DNA glycosylases in vitro suggests that these enzymes may be responsible for repair of these mutagenic lesions in vivo, and thus constitute important contributors to genetic stability.
Gros
Laurent
L
Groupe Réparation de l'ADN, UMR8113 CNRS, LBPA-ENS Cachan, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Ishchenko
Alexander A
AA
Saparbaev
Murat
M
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D017382:Reactive Oxygen Species; D044502:Thymine DNA Glycosylase / Q000378:metabolism
D018736:DNA Adducts; C015196:N(2),3-ethenoguanine; D017382:Reactive Oxygen Species; C004981:1,N(6)-ethenoadenine; C051143:3,N(4)-ethanocytosine; D006147:Guanine; D003596:Cytosine; D045647:DNA Glycosylases; D044502:Thymine DNA Glycosylase; C113921:mismatch-specific thymine uracil-DNA glycosylase; D000225:Adenine