Potentially Mutagenic Lesions

To determine whether excision-repair processes can also protect cells from potentially mutagenic DNA damage induced by UV light, we compared the 

Comparative studies of the frequency of mutations to AG or TG resistance induced in normal and XP cells by exposure to V-AcO-AAF or to reactive metabolites of several carcinogenic polycyclic hydrocarbons, e.g., benzo[a]- 

FIGURE 7. Comparison of the cytotoxic and mutagenic effect of increasing doses of UV irradiation in normal fibroblasts (NF) and in XP cells with no detectable excision-repair capacity (XP12BE) or able to carry out excision at a reduced rate (16% of normal) (XP12BE) See Section 2.2 for the procedures used to measure cytotoxicity and Section 2.3.1 for the in situ procedures used to detect the frequency of induction of mutations to AG resistance. Taken from Maher et with permission. 

XP cells are significantly more susceptible than are normal cells to the mutagenic action of these chemical carcinogens. 

TABLE 1. HPRT Activity of Randomly Isolated AG- or TG-Resistant Clones 

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An elegant and extremely sophisticated set of mutation-avoidance mechanisms operates within cells so effective are these that only once in 103-108 possibilities is a potentially mutagenic lesion not circumvented. These mechanisms operate at three distinct times during the cell cycle before, during, and shortly after ENA replication. 

The ability of Polt/ and Polt to bypass a variety of structurally diverse and potentially mutagenic lesions in vitro has been analyzed extensively. These biochemical studies revealed that the efficiency and pattern of nucleotide incorporation opposite DNA damaged sites is distinct for the two RadSO paralogp. In some cases, Polt/ readily bypasses a lesion, whereas Polt does it inefficiently, or not at all. An example of Poltj s and Polt s disparate TLS activities is observed at thymine CPDs and cisplatin-induced dG intrastrand crosslinks. Polt/ efficiently facilitates robust bypass of both CPDs (Johnson et aL, 2000c Masutani et aL, 2000 McGuUoch et aL, 2004) and platinum-GG cross links (Vaisman et aL, 2000) in vitro, whereas Polt bypasses the GPD in a limited manner (Tissier et aL, 2000a) that is sequence context dependent (Vaisman et al., 2003) and is incapable of nucleotide incorporation opposite a cisplatin adduct (McDonald et al., 2001). 

Figure 15. DNA molecular alteration processes induced by UV-B radiation that distort the helical structure and cause severe, potentially deadly mutagenic lesions.

The mutagenic lesions 2-aminofluorene and 2-acetylaminofluorene attached to the C of dG have been examined for their mutagenic potential. The lesions induce G T transversions and G A transitions depending upon the flanking base. 

The (6—4) photolyase was first discovered in D. melanogaster (Todo et aL, 1993, 1996). Subsequently it was found in Xenopus laevis, rattlesnake (Kim et al, 1994), zebrafish, and A. thaliana, among many other species (Todo, 1999). Of special interest, the enzyme has not been found in birds and mammals (Hsu et at, 1996). Thus, humans lack both photolyase and (6-4) photo lyase and cannot carry out photorepair of UV-induced DNA damage. They rely solely on nucleotide excision repair for eliminating these potentially mutagenic and carcinogenic lesions from their DNA. 

Evidence That Excision Repair Can Eliminate Potentially Cytotoxic and Mutagenic Lesions From DNA... 

The complex [Fe2(SMe)2(NO)4] has been found to have only weak mutagenic properties when employed alone (149, 152-154), although it potentiated the action of 3-methylcolanthrene (154). A recent study of the effects of [Fe2(SMe)2(NO)4] and Me(PhCH2)NNO upon mice found (155) that while [Fe2(SMe)2(NO)4] alone caused no lesions in the esophagus or the forestomach, it markedly enhanced the lesion count induced by Me(PhCH2)NNO thus it promotes the tumorigenic properties of Me(PhCH2)NNO. 

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