6-4 Pyrimidine-pyrimidone

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... 

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). 

Thymidine cis-syn dimer pyrimidine-pyrimidone photoadduct Spector 1997... 

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,... 

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

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. 

Another type of dimeric lesions are pyrimidine-pyrimidone (Pyr[6-4]Pyr) dimers formed by a Paterno-Biichi-type reaction at dipyrimidine sites between the C(5)=C(6) double bond of the first pyrimidine and the C(4)=0 carbonyl group of the second base. This kind of dimerization is demonstrated in Scheme 8.2 for the case of adjacent thymine moieties. 

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. 

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