Pyrimidine dimers mechanism

Zhang RB, Eriksson LA (2006) A triplet mechanism for the formation of cyclobutane pyrimidine dimers in UV-irradiated DNA. J Phys Chem B 110 7556-7562... 

Scheme 2 Mechanism of repair of cyclobutane pyrimidine dimers (CPD) by a CPD photolyase. 8-HDF 8-hydroxy-5-deazaflavin, ET electron transfer. FADH reduced and de-protonated flavin-coenzyme...

An ab initio study on the structure and splitting of the uracil dimer anion-radical (see Scheme 3.72, R = H) gives preference to the one-step mechanism (Voityuk and Roesch 1997). Anion-radical anions of the pyrimidine dimers cleave with rate constants in excess of 10 s ... 

The mechanism of dimer cleavage has been probed in model systems, including bifunctional ones in which a sensitizer (e.g., indole) is linked to the pyrimidine dimer. Work on a linked dimer (64), suggested that a dimer radical cation is a discrete (short-lived) minimum. ... 

Pyrimidine dimers and other forms of DNA damage can be removed by a general excision repair mechanism. The first reaction in this form of repair involves forming nicks about the damaged region of the DNA. In (a) we see the mode of incision of UV-irradiated DNA by the pyrimidine-dimer-specific glycosylase and AP endonuclease... 

There has been considerable interest in the mechanism of action of DNA photolyase enzymes, which repair pyrimidine dimers in damaged DNA via action of visible light. Several model reactions have given credence to a possible SET pathway. For example, Falvey and coworker reported that the photochemical reaction of dimer 35 with FADH2 results in a retro [2 + 2] cycloaddition according to Scheme 2269. 

An ab initio study on the structure and splitting of the uracil dimer anion radical (see Scheme 3-66 and keep R = H) gives preference to the one-step mechanism (Voityuk Roesch 1997). Anion radical anions of the pyrimidine dimers cleave with rate constants in excess of 106 sec 1 (Yeh Falvey 1991). However, the cyclobutyl dimer of a quinone, dithymoquinone, also cleaves upon single-electron reduction but much more slowly than the pyrimidine dimers (Robbins Falvey 1993). It is truly an unresolved issue as to why the anion radical cleavage depicted in Scheme 3-66 is so facile. Water participation can probably decrease the barrier of the cycloreversion on physiological conditions (Saettel Wiest 2001). 

The electron transfer induced cleavage of cyclobutane systems is of interest also in connection with photoreactivation, a repair mechanism for photo-damaged DNA. Upon exposure to UV light, DNA may be damaged by the formation of cyclobutane links between adjacent thymine units. The resulting dimers are cleaved, and DNA is restored, by a photoreactivating enzyme in the presence of near UV or visible light. The mechanism of reactivation may involve electron transfer, either to or from the pyrimidine dimer [258-260]. 

Spore Photoproduct Lyase. The DNA in spores is in A-form because of dehydration. As a consequence, when spores are exposed to UV, the stereochemistry of the bases is not conducive to the formation of cyclobutane pyrimidine dimers or (6-4) photoproducts. Instead, UV induces the formation of 5-thyminyl-5,6-dihydrothymine or spore photoproduct (SP). This lesion is repaired by a 40-kDa enzyme called SP lyase. The enzyme is an iron-sulfur [4Fe-4S] protein that employs S-adenosyl-methionine (AdoMet) as a catalytic cofactor and carries out repair by a radical mechanism (6) (Fig. 2). In this mechanism, the reduced [Fe-S] center cleaves AdoMet to generate a 5 -deoxyadenosyl radical intermediate and methionine. The radical then abstracts an H-atom from C-6 of the SP. The resulting substrate radical undergoes bond cleavage to generate a product radical. The latter abstracts an H-atom from the 5 deoxyadenosine to form canonical thymines and a 5 deoxyadenosyl radical. Finally, the catalytic cycle is closed by electron transfer back to the [Fe-S] cluster concomitant with the formation of AdoMet (6). 

The literature documents various situations in which C deamination is enhanced. These situations include the presence of C in cyclobutane pyrimidine dimers (a form of DNA damage caused by exposure to UV radiation see later discussion) or in mis-pairings with other bases or with alkylated bases (1). Cytosine deamination is also promoted in the presence of nitrons acid, a reaction that although not considered in this review, has lent much to our understanding of possible chemical mechanisms of spontaneous deamination (1). 

Ultraviolet light produces pyrimidine dimers in human DNA, as it does in E. coli DNA. Furthermore, the repair mechanisms are similar. Studies of skin fibroblasts from patients with xeroderma pigmentosum have revealed a biochemical defect in one form of this disease. In normal fibro-blasts, half the pyrimidine dimers produced by ultraviolet radiation are excised in less than 24 hours. In contrast, almost no dimers are excised in this time interval in fibroblasts derived from patients with xeroderma pigmentosum. The results of these studies show that xeroderma pigmentosum can be produced by a defect in the excinuclease that hydrolyzes the DNA backbone near a pyrimidine dimer. The drastic clinical consequences of this enzymatic defect emphasize the critical importance of DNA-repair processes. The disease can also be caused by mutations in eight other genes for DNA repair, which attests to the complexity of repair processes. 

The photosensitized monomerization of thymine dimers has been achieved in the presence of reduced flavin,and pyrimidine dimers undergo cleavage by light-utilizing enzymes which are thought to act by a photoinduced electron transfer mechanism. ... 

As a consequence of photodamage to DNA there is still considerable interest in the photochemical dimerization of pyrimidine derivatives. Thus, the synthesis of the pyrimidine dimers (157), (158) and (159) has been carried out by irradiation of the pyrimidine derivative (160). Sugiki et al. have studied the photochemical dimerization of the long-chain substituted thymine derivatives (161). The results of the measurement of the reduction potentials of thymine and cytosine cyclobutane dimers have been reported. In addition the electron-transfer-induced ring cleavage by electron donation from suitable sensitizers of the adducts (162) and (163) has also been examined. Calculations have been carried out on the photo-induced repair mechanism in DNA both by direct irradiation and by the use of SET induced photocleavage. ... 

Two modes of excision repair, (a) Escherichia coli mechanism. Two incision steps are followed by gap-filling and displacement by polymerase 1. (b) Micrococcus luteus mechanism. A pyrimidine dimer glycosylase breaks an N-glycosidic bond and makes a single incision. Pol 1 displaces the strand, which is removed by an exonucleolytic event. In both mechanisms, the final step is ligation. 

Clayton DA, Doda JN, Friedberg EC (1974) The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci USA 71 2777-81 Croteau DL,BohrVA (1997) Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem 272 25409-12... 

Figure 7. Measured and modeled profiles of cyclobutane pyrimidine dimers (CPD) for water columns with varying intensities of vertical mixing (a) Gulf of Mexico, 8 September 1994, mixed layer 20 m, wind speed low (2 m s ) (b) Gulf of Mexico, 7 September 1994, mixed layer 20 m, wind speed high (8 m s ) (c) Gerlache Strait, Antarctica, 6 October 1996, mixed layer 25 m, wind speed high (8 m s 0- Modeled profiles are for damage (CPD formation) only, damage plus photoreactivation only, and damage and all repair mechanisms (photoreactivation and excision repair). [From Jeffrey et al. and Huot et al. 82.]...

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