Tandem Base Lesions

Only limited information is available on nracil hydroperoxides that are likely to be generated in a similar way to thymine analognes by initial "OH radical addition in aerated aqueous solutions. This is likely due to the higher instabihty of these peroxides. Evidence has been recently provided for the implication of the 5-peroxy-5,6-dihydrouracil-6-yl radical in the formation of tandem base lesions. 

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. 

Boudaiffa B, Cloutier P, Hunting D, Huels MA, Sanche L (2002) Cross sections for low-energy (10-50 eV) electron damage to DNA. Radiat Res 157 227-234 Bourdat A-G, Douki T, Frelon S, Gasparutto D, Cadet J (2000) Tandem base lesions are generated by hydroxyl radical within isolated DNA in aerated agueous solution. J Am Chem Soc 122 4549-4556... 

Figure 6 Detection ofthe 8-oxoGua/formylamine tandem lesions in isolated DNA exposed to gamma radiation in aerated aqueous solution. DNA was digested by a mild enzymatic treatment in order to release the lesions without cleavage of the phosphodiester bond. The sample was then injected onto a reverse phase HPLC column. The detection was provided by a mass spectrometer monitoring the main fragmentation ofthe two tandem base lesions.

Bourdat, A.G., Douki, T., Frelon, S., Gasparutto, D., and Cadet, J. (2000) Tandem base lesions are generated by hydroxyl radical witbin isolated DNA in aerated aqueous solution. J. Am. Chem. Soc., 122, 4549-4556. 

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. 

Bergeron F, Anvre F, RadiceDa JP, Ravanat J-L. HO radicals indnce an nnexpected high proportion of tandem lesion base lesions refiactory to repair by DNA glycosylases. Proc Nat Acad Sd USA. 2010 107 5528—5533. 

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. ... 

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... 

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... 

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. 

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). 

The main oxidation reactions of the 2-deoxyribose of DNA are mediated by "OH that are able to abstract hydrogen atoms from most of the positions with the exception of the methylene group at C2, which is a poorly reactive site [12, 14, 112], An abundant literature is available on the degradation pathways that are derived from the reactions of osidic carbon-centered radicals and that lead in most cases to the formation of strand breaks [12, 14, 112], However, there is one major exception that concerns the chemical reactions of the CT radical that is the precursor of 2-deoxyribonolactone [113]. Here, emphasis is placed on reactions of C4 and C5 radicals that may lead to the formation of base modifications either as tandem lesions or clustered damage. 

---