Pyrimidine pyrimidone photoproduct

DNA strongly absorbs UV radiation, especially mid-range UVB (290 to 320 nm) radiation. Two major DNA lesions are induced following UV exposure, pyrimidine dimers and 6-4 pyrimidine-pyrimidone photoproducts. Because the action spectrum (induction of a biological activity as a function of wavelength) for erythema closely matches the action spectrum for pyrimidine dimer formation, DNA is believed to be the chromophore for sunburn.6 Pyrimidine dimer formation, or more properly, the failure to adequately repair dimers after solar irradiation is also the primary cause of sunlight-induced skin cancer formation.7-8... 

The (6-4) pyrimidine-pyrimidone photoproducts, which are the second most abundant... 

Chvio, P., Fourrey, J.-L., and Gasche, J., Novel insight into the stereochemical pathway leading to (6—4) pyrimidine-pyrimidone photoproducts in DNA, Tetrahedron Lett., 33, 1615,1992. 

Figure 12.1 Structures of (a) cyclobutane pyrimidine dimer (ToT), (b) pyrimidine (6-4) pyrimidone photoproduct ((6-4)pp). (c) The scheme of the catalytic cycle for the repairing of ToT dimers by DNA photolyase 114]...

There are two major types of DNA damage following UV radiation cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts that are often simply called (6-4) photoproducts. Formation of these UV lesions may be influenced by the DNA sequence. Nevertheless, in general, CPDs are more abundant than (6-4) photoproducts in UV irradiated DNA. For example, in UVC-irradiated DNA, the overall ratio of CPDs to (6-4) photoproducts is about 3 1. 

Another major form of base damage generated in DNA by UV light is one in which the C6 position of a 5 pyrimidine is covalently linked to the C4 position of the 3 adjacent pyrimidine (Fig. 6). These lesions [which are readily detected by their lability in alkaline conditions at 80-100° C (43)], are called pyrimidine-pyrimidone [6-4] adducts, or simply [6-4] photoproducts ([6-4]PP). The pyrimidine planes in ([6-4]PP) are almost perpendicular. Hence, they result in prominent distortions of the double-helical structure of DNA. ([6-4]PP) can involve adjacent TC, CC, or (less often) TT sequences. Their formation at CT sequences is infrequent. Cytosine methylation at the C5 position inhibits the formation of [6-4]PP (44). The yield of [6-4]PP is proportional to the incident UV fluence in the range 100-500 J/m and continues to increase after exposure to several thousand J/m (1). In UV-C irradiated DNA, the ratio of CPD [6-4]PP is 3 1 (1). 

Pfeifer GP, Drouin R, Riggs AD, Holmquist GP. In vivo mapping of a DNA adduct at nucleotide resolution detection of pyrimidine (6-4) pyrimidone photoproducts by ligation-mediated polymerase chain reaction. Proc. Natl. Acad. Sci. U.S.A. 1991 88 1374-1378. 

Clingen, P. H., Arlett, C. F., Roza, L., Mori, T. Nikaido, O., Green, M. H. L. 1995. Induction of cyclobutane pyrimidine imers, pyrimidine(6-4)pyrimidone photoproducts and Dewar valence isomers by natural sunlight in normal human mononuclear cells. Cancer Res. 

The dinucleotide phosphoramidite building block 185 can be utilised to synthesise oligomers containing a pyrimidine(6-4)pyrimidone photoproduct. The unstability of the photoproduct to base necessitated the use of 4-/-(butylphe-noxy)-acetyl protecting groups for dA, dG and dC allowing deprotection of the oligomers in aqueous ammonia at room temperature in two hours. 

Figure 2. Structure of two photoproducts, formed by UV-B exposure to DNA. (A) Cyclobutane pyrimidine dimer (thymine dimer). (B) Pyrimidine (6-4) pyrimidone photoproduct (6-4 PP). [Redrawn from Friedberg et ai. 38.]...

LeClerc, J.E., Borden, A., and Lawrence, C.W. (1991) The thymine-thymine pyrimidine-pyrimidone (6-4) ultraviolet light photoproduct is highly mutagenic and specifically induces 3 thymine-to-cytosine transitions in Escherichia coli. Proc. Natl. Acad. Sci. USA, 88,... 

Vreeswijk, M.P., van Hoffen, A., Westland, B.E., Vrieling, H., van Zeeland, A.A., and Mullenders, L.H. (1994) Analysis of repair of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts in transcriptionally active and inactive genes in Chinese hamster cells. J. Biol. Chem., 269, 31858-31863. 

Brash, D. E., Franklin, W. A., Sancar, G. B., Sancar, A., and Haseltine, W. A. (1985). E. coli photolyase reverses cyclobutane pyrimidine dimers but not pyrimidine-pyrimidone (6-4) photoproducts. / Biol. Chem. 260, 11438-11441. 

Chen, J. J., Mitchell, D. L., and Britt, A. B. (1994). A light-dependent pathway for elimination of UV-induced pyrimidine (6-4) pyrimidone photoproducts of Arabi-dopsis. Plant Cell 6, 1311-1317. 

The dimerization can, in prindple, lead to three isomers cis-syn, trans-syn I, and trans-syn II however, due to the constraints imposed by the DNA double strand, the cis-syn dimer shown in Scheme 3.36 is the major photoproduct [144]. Pyrimidine-pyrimidone (Pyr[6-4]Pyr) dimers represent another type of dimeric lesion that is formed by a Paterno-Biichi-type reaction at dipyrimidine sites between the... 

Studies on DNA damage include also examples of photoisomerization reactions. As explained in section 5.2.3, UV-irradiated DNA undergoes photocycloaddition processes which result in the formation of different photoproducts. Among the photoadducts, the pyrimidine (6-4) pyrimidone dimer is the most commonly found in experiments. This species can further evolve, generating the Dewar isomer via a photoinduced process. The interconversion mechanism between both photoisomers has been analysed by Ai et alP ... 

Dimerizations between adjacent pyrimidine bases are by far the most prevalent photoreactions resulting from UVC or UV-B irradiation of DNA (Table 140.1), with the relative induction dependent on wavelength, DNA sequence, and protein-DNA interactions. The major photoproducts in DNA are the cydobutyl pyrimidine dimer (CPD), formed through the exdted triplet state, and the pyrimidine-(6-4)pyrunidone dimer [(6-4)PD], formed from a Patemo-Biichi reaction. The (6-4) photoproduct undergoes further UV-B-dependent conversion with its valence photoisomer, the Dewar pyrirnidinone. In addition to the major photoproducts, rare dimers may also form, such as the adenine-thyrnine heterodimer or the 2-imida-zolone(5 )pyrimidone product, another photoisomerization product of the (6—4)PD. 

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