Abasic site formation

Table I. Abasic Site Formation Induced by the Reaction of t-BuOOH with Hemoglobin" or EDTA/Fe ...

Figure 3. Abasic site formation of the reaction of t-BuOOH with hemoglobin. Reproduced with permission from reference 17. Copyright 2000 Elsevier Science Ireland Ltd,...

As described before, a smaller substituent at the 2 -P position of 2 -deoxycytidine is tolerant only for cytotoxicity. Introduction of an electron-withdrawing group into the 2 -P position would increase the acidity of the 2 -a proton. If such a nucleoside is enzymatically phosphorylated and incorporated into DNA molecules, the electron-withdrawing group becomes P to the phosphate diester in the DNA molecule. In this case, P-elimination would produce (i) DNA strand-breaks or (ii) abasic site formation as illustrated in Fig. S. Together with this hypothesis, the nucleoside 5 -polyphosphates would also inhibit ribonucleotide reductase and/or DNA polymerases. Since strand-breaks in DNA by radiation thenq)y have been hypothesized to produce tumor cell death, it is worth examining whether the nucleoside... 

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... 

Smith RA, Sysel IA, Tibbels TS, et al. 1988. Implications for the formation of abasic sites following modification of polydeoxycytidylic acid by acrolein in vitro. Cancer Lett 40 103-109. 

The removal of an altered base by the glycosylase results in the formation of an abasic site (AP site) (sometimes also referred to as an apurinic or apyrimidinic site). The AP site is acted upon by an AP endonuclease that makes an incision in the damaged strand by hydrolyzing the phosphodiester bond 5 to the AP site (Figure 23.5). Alternatively, some glycosylases have an associated lyase activity that incises... 

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.)...

Figure 21-30. The potential energy surface along the pathway leading to the formation of the abasic site (Pabasic). The energy is in kcal/mol-1, except when otherwise indicated (Scheme 2 and Figure 2 of ref. [78]. Reprinted with permission.)...

An intrastrand cross-link formed by cisplatin and adjacent guanine residues causes an unusally distorted base pair (bp) step, known as the Lippard bp step. A study of the effects of neighbouring nucleotides to the cross-linked G G has shown that the 3 -nucleotide has little effect, but the 5 -nucleotide has a dramatic effect. The 5 residue always maintains an S pucker, but the canting varies, depending on the substituent. Bleomycin causes two major lesions to DNA, formation of a 4 -keto abasic site and strand cleavage to yield a 3 -phosphog-lycolate and a 5 -phosphate. As a model for the 4 -keto abasic site, an NMR structure of a 13-mer DNA duplex containing an abasic site has been reported." It was found that for both the a- and p-anomers, the abasic site was extrahelical, and that the duplex showed very little distortion to the backbone. This was discussed in terms of repair of such lesions in vivo. 

Three of the deoxyribose carbon centered radicals, dRib(C3 -H), dRib(C4 -H), and dRib(C5 -H), give rise to prompt SSB via a phosphate elimination reaction. The strand break mechanism for the dRib(CI -H) radical differs substantially. Like the three radicals above, it will release a free unaltered base but instead of forming a strand break, a subsequent one-electron oxidation results in deoxyribonolactone (dRibonoLac) formation (Fig. la) [1,18].This abasic site is quite stable. Heat and a catalyst, such as spermine, turn this lesion into a strand break plus 5-methylenefuranone (SMFur) [18]. The later is a signature end product of Cl sugar damage. 

Ionizing radiation induces the formation of base damage, i.e. oxidized and reduced bases and abasic sites (Chapter 12), which are repaired by BER. Single strand breaks (SSB) which are produced by ionizing radiation but also as repair intermediates at the early steps of BER (Fig. 3), are processed by BER. 

Oxidation of the 2 -position is perhaps the least-studied 2 -deoxyribose oxidation chemistry and results in the formation of a D-erythrose abasic site (Figure 2.4) [163, 164]. With implications for the biological response to 2 -deoxyribose oxidation, this abasic site is substantially more stable to hydrolysis than the native and other oxidized abasic sites, with a half-life of 3h in 0.1 M NaOH at 37°C [165],... 

Recent studies have revealed novel facets of 4 -oxidahon of 2-deoxyribose in DNA. In all cases, one pathway leads to a 2 -deoxypentos-4-ulose abasic site (Figure 2.4). In addition, the other two pathways both entail formation of a strand break... 

Sczepanski, J.T., Jacobs, A.C., and Greenberg, M.M. (2008) Self promoted interstrand cross-link formation by an abasic site./. Am. Chem. Soc., 130, 9646-9647. 

However, alkylation at the N7 position weakens the glycosidic bond and this often leads to depurination (i.e., formation of an abasic site). Nevertheless, the possibility that N7-alkylG adducts could be directly miscoding (at some level) has not been tested carefully and cannot be dismissed. The alkylation changes the pfCa of the pyrimidine ring atoms of the purine and could induce mispairs via minor tautomers [138]. 

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