Tandem lesion

In some circumstances, DNA radical lesions can react with an adjacent base or the sugar residues. In these cases, a single radical hit can be transformed into two adjacent damage sites on the DNA. The resulting tandem lesions may present special challenges to DNA replication and repair systems. ... 

Reactions involving T(—H) in dinucleotides and single-stranded oligonucleotides led to the formation of tandem lesions in deaerated aqueous solution involving covalent bond formation between the 5-methyl and C-8 of The d(G T)... 

The Greenberg laboratory has studied the fate of T(—H) within duplex DNA and have discovered that tandem lesions (intrastrand cross-links) are not produced and... 

Tandem lesion, where C(8) of G is bound to the methyl group of T... 

This addition reaction is not restricted to a-hydroxyalkyl radicals, although this type of radical has been most widely investigated. Thus, allylic radical derived from 5MeCyt (Zhang and Wang 2003) and radicals derived from amino acids (Elad and Rosenthal 1969) are also reported to undergo this reaction. In DNA, they play a role in the formation of tandem lesions (Chap. 12.5), and it is likely that this kind of reaction contributes to free-radical-induced DNA/DNA and DNA/protein cross-linking. 

In DNA, the C(l )-H is hidden in the minor groove and hence difficult to access by reactive free radicals such as OH (Chap. 12.2). If the above type of reaction would occur within DNA, it would lead to a tandem lesion (for their biological importance see Chap. 12.5). 

In Thy-Gua and Thy-Ade dinucleosides, the allylic Thy-derived radical gives rise to a tandem lesions denoted as GAT, TAG, AAT and TAA [e.g., reaction (219) Bellon etal. 2002],... 

These studies have been extended to the photooxidation of d(TpG) by riboflavin and methylene blue, and again Z and its precursor Iz have been characterized (Buchko et al. 1995b). When d(TpG) is photooxidized with benzophenone or menadione, an additional product, , is formed [reactions (305) and (305) Delatour et al. 1999], It constitutes a tandem lesion. 

Bellon S, Ravanat J-L, Gasparutto D, Cadet J (2002) Cross-linked thymine-purine base tandem lesions synthesis, characterization, and measurement in y-irradiated isolated DNA. Chem Res Toxicol 15 598-606... 

The number of studies on ssODNs is rather low, but important information as to the formation of tandem lesions has been obtained with these systems. 

In an extension of this study, some further tandem lesions were detected in d(CpGpTpA) and d(CpApTpG) (Box et al. 1998). The cross-linked tandem base lesions shown below are only formed in the absence of 02. 

Box HC, Budzinski EE, DawidzikJB, Wallace JC, lijima H (1998) Tandem lesions and other products in X-irradiated DNA oligomers. Radiat Res 149 433-439 Budzinski EE, DawidzikJB, Rajecki MJ, Wallace JC, Schroder EA, Box HC (1997) Isolation and characterization of the products of anoxic irradiation of d(CpGpTpA). Int J Radiat Biol 71 327-336 Candeias LP, O Neill P, Jones GDD, Steenken S (1992) Ionization of polynucleotides and DNA in aqueous solution by 193 nm pulsed laser light identification of base-derived radicals. Int J Radiat Biol 61 15-20... 

Clustered Lesions and Damage Amplification Reactions (Tandem Lesions) 391... 

The main types of damage that can be formed in DNA (base damage, apy-rimidnic/apurinic (AP) site, single-strand break (SSB), double-strand break (DSB), tandem lesions and various clustered lesions) are shown schematically in Fig. 12.1. There are, however, further lesions such as DNA/DNA and DNA/pro-tein cross-links. 

Nearly all modifications that have been detected on the model level (Chap. 10) are also found in free-radical damaged DNA. Obviously the DNA-bound lesions are much more difficult to detect, and there is an ongoing discussion as to the best procedure of their excision (Chap. 13.2 for a review on the excision and repair of base lesions in vivo see Wallace, 2002). Mechanistic details concerning the formation of the base lesions have been discussed in Chapters 10 and 11, and only some additional information will be given below and in the section on clustered lesions where the phenomenon of tandem lesions, two damaged bases that are formed side by side, is dealt with. The yields of damaged bases formed upon y-irradiation in aqueous solution, as has been determined by the GC-MS/SIM technique, are compiled in Table 12.5. 

Another damage amplification reaction has been observed with a dinucleotide model which allowed to generate a Thy-5-yl radical specifically. In the presence of 02, it causes the formation of the 2-dRL lesion at the adjacent nucleotide unit (Chap. 10.3). Based on this, -OH-addition to C(6) of T and C could give rise to this tandem lesion also in DNA (as yet not detected). 

It is as not known to what extent the observed formation of 2-dRL in DNA is due to such a tandem lesion (see also Sect. 12.4.4 note that HI is hidden in the minor groove (Sect. 12.2) and not very likely to be attacked by freely-diffusing reactive radicals such as -OH). 

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