Aldehydes abasic sites

Besides the direct oxidation products of base residues of DNA, such as the oxidation of thymine (43) and guanine (160) residues meutioued in Sections IV.B.2 and IV.B.3, ROS and other factors may bring about detachmeut of base residues from the DNA strand, leading to formation of aldehyde abasic sites on the main chain, as shown in... 

Until recently, all enzymes that catalyze the cleavage of phosphate ester bonds were assumed to be phosphohydrolases, i.e., the cleavage reaction occurs by hydrolysis of a phosphodiester bond to generate ends containing a phosphate monoester and a hydroxyl group. This assumption has now been shown to be incorrect for enzymes that introduce strand breaks on the 3 -side of aldehydic abasic sites (also referred to as apurinic, apyrimidinic, or simply AP sites) during DNA repair. Despite the title of this chapter, the mechanism of the strand cleavage reaction will be briefly described. 

Fig. 14). Whereas a mixture of anomeric hemiacetals constitutes the major contribution to the structure of an aldehydic abasic site (777), the syn stereochemical course indicates that the strand cleavage occurs from an acyclic species such as the aldehyde or an activated acyclic species derived from the aldehyde, i.e., an imine (770). 

Mazumder, A., Gerlt, J. A., Absalon, M. J., Stubbe, J., Cunningham, R. P., Withka, J., and Bolton, P. H. (1991). Stereochemical studies of the beta-elimination reactions at aldehydic abasic sites in DNA Endonuclease III from Escherichia coli, sodium hydroxide, and Lys-Trp-Lys. Biochemistry 30, 1119-1126. 

The abasic sites (3, Scheme 8.2) resulting from the loss of alkylated bases from DNA are both cytotoxic and mutagenic. " The cyclic acetal (3) exists in equilibrium with small amounts (—1%) of the open chain aldehyde (4). The acidic nature of a-proton in the aldehyde form of the abasic lesion facilitates 3-elimination of the 3 -phosphate residue to yield a strand break. " This reaction occurs with a half-life of about 200 h under physiological conditions (pH 7.4, 37°C), but can be accelerated by heat, basic conditions, or the presence of various amines. " ... 

Figure 23.7. Structure of an AP site (center) and structures produced by 5 AP endonuclease activity (left) or lyase activity (right). These are formed in double-strand DNA, but only one strand is represented in the figure. 5 AP-endonuclease activity results in the formation of a 5 -deoxyribose-phosphate end (5 -dRP), which must be subsequently processed by a dRPase (see text). Lyase activity results in the formation of 3 -unsaturated aldehydic a, P, 4-hydroxy-2-pentenal end, which must be subsequently acted upon by a 5 AP endonuclease. (Reproduced with permission from Boiteux, S., and Guillet, M. Abasic sites in DNA repair and biological consequences in Saccharomyces cerevisiae. DNA Repair 3,1-12, 2004.)...

Introduction of biotin markers at abasic aldehyde sites in DNA, resulting from oxidative damage (equation 59,... 

---