Mutagenesis, Vol. 16, No. 1, 1-6,
January 2001
© 2001 UK Environmental Mutagen Society/Oxford University Press
Effects of photoreactivation of cyclobutane pyrimidine dimers and pyrimidine (6–4) pyrimidone photoproducts on ultraviolet mutagenesis in SOS-induced repair-deficient Escherichia coli
1 Biological Institute, Graduate School of Science, Tohoku University, Sendai 980-8578, 2 Department of Radiation Biophysics, Nagasaki University School of Medicine, Nagasaki 852-8523 and 3 Division of Radiation Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934, Japan
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Abstract |
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Using purified photolyases for pyrimidine (6–4) pyrimidone photoproducts [(6–4)PP] and cyclobutane pyrimidine dimers (CPD), the effects of photoreactivation on mutagenesis were examined in the supF gene on a plasmid transfected into repair-deficient SOS-induced Escherichia coli host cells. More than 95% of CPD and (6–4)PP were removed from plasmid DNA by treatment with CPD photolyase and (6–4)photolyase, respectively. In each photolyase treatment, base substitutions at dipyrimidine sequences were predominantly observed. Of the singlebase substitutions observed after CPD photoreactivation, 83% were A:T
G:C transitions at 5'-TT-3' sites. After (6–4)photolyase treatment, 81% were G:CA:T transitions at 5'-CC-3' and 5'-TC-3' sequences. Thus, the major mutagenic photoproducts of single-base substitutions were CPD at 5'-CC-3' or 5'-TC-3' sites and (6–4)PP at 5'-TT-3' sites. Tandem double mutations occurred mainly at 5'-CC-3' sites and were CPD-photoreactivated, suggesting that CPD at 5'-CC-3' was responsible for tandem double mutations. After photoreactivation of both CPD and (6–4)PP, single-base substitutions were primarily G:CA:T transitions at 5'-CC-3' or 5'-TC-3' sites and A:TG:C transitions at 5'-TT-3' sites, and secondarily G:CT:A transversions at 5'-CC-3' sites, G:CC:G transversions at 5'-CC-3' sites and A:TT:A transversions at 5'-TT-3' sites, which were essentially the same as those observed after photoreactivation of CPD alone, (6–4)PP alone and without photoreactivation. Thus, these transversions were not derived from unknown UV adducts but from incompletely repaired CPD and (6–4)PP. |
Introduction |
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Previous studies on viral and cellular oncogenes have provided strong evidence that mutations can play a fundamental role in cellular transformation, carcinogenesis and many inheritable diseases (Bishop, 1983
; Santos et al., 1983). Information concerning the specificity of a particular mutagen may yield insight into the nature of the premutational lesions as well as the actual mutagenic pathways involved. One of the most extensively studied mutagens, UV irradiation, has been shown to cause mutations in both bacterial and mammalian cell systems (Wood et al., 1984; Miller, 1985; Bredberg et al., 1986; Protic-Sabljic et al., 1986). Many UV-induced photoproducts in DNA have been well characterized (Cadet et al., 1992) and many of the biochemical and genetic effects of UV light have led to a detailed understanding of the SOS functions in Escherichia coli, a process that is required for UV mutagenesis (Smith and Walker, 1998). Most of the UV-induced mutations appear to involve specific DNA lesions formed at dipyrimidine sequences (Brash and Haseltine, 1982; Wood et al., 1984; Miller, 1985; Bredberg et al., 1986; Protic-Sabljic et al., 1986; Brash et al., 1987). However, the type of damage chiefly responsible for UV mutagenesis has not been conclusively identified. Identification of the UV photoproduct that plays a dominant role in UV mutagenesis will significantly further our understanding of the biological consequences of UV irradiation.
The two most prevalent classes of UV-induced photoproducts in DNA are pyrimidine (6–4) pyrimidone photoproducts [(6–4)PP] and cyclobutane pyrimidine dimers (CPD) (Cadet et al., 1992). Both of these products involve dimerization of adjacent pyrimidines on the same DNA strand. Although both (6–4)PP and CPD have been indicated as contributing to UV mutagenesis, there is disagreement in the literature as to whether the major mutagenic photoproduct induced in DNA by UV light is (6–4)PP or CPD. Evidence that (6–4)PP may play a dominant role in UV-induced transition mutagenesis has been obtained for bacteria and lambda phage (Brash and Haseltine, 1982; Wood et al., 1984). However, other evidence suggests that CPD are also capable of targeting mutations in bacteria, lambda phage and mammalian cells (Kunz and Glickman, 1984; Lawrence et al., 1985; Yamamoto et al., 1985; Protic-Sabljic et al., 1986; Brash et al., 1987; Hutchinson et al., 1988). The situation is further complicated by the suggestion that additional UV-induced lesions such as purine-containing dimers or Dewar valence isomers are mutagenic lesions (Gallagher and Duker, 1986; Cadet et al., 1992).
We studied the changes in UV mutagenesis of the plasmid pTN89, assayed in SOS-induced cells, with in vitro enzymatic photoreactivation. We used the E.coli photolyase (Yamamoto et al., 1983) and Arabidopsis thaliana (6–4)photolyase (Nakajima et al., 1998), which specifically resolve CPD and (6–4)PP, respectively, leaving normal DNA structures without affecting the other lesions (Todo et al., 1993; Sancar, 1994; Todo et al., 1997). Thus, all observations such as the type, location and frequency of mutations are obtained with the same coherent genetic system, so that they can be directly compared.
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Materials and methods |
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Bacterial strains and plasmids
The E.coli strain used in the experiment was NKJ3000 (as JM107 but phr20::Kn uvrA::Kn) (Nakajima et al., 1998
). E.coli KS40 (lacZam gyrA rpsL) (Akasaka et al., 1992), derived from MBM7070 (Seidman et al., 1985), harbors pOF105 (Obata et al., 1998) carrying gyrAam and rpsLam genes in the pACYC plasmid and is designated as KS40/pOF105. E.coli XL1-BlueMRF' (Stratagene, La Jolla, CA) was used as the host for M13KO7, which was used to prepare single-stranded DNA for DNA sequencing. Plasmid pTN89 carries the tyrosine amber suppressor tRNA (supF) gene as a mutational target, ampicillin resistance gene and f1 replication origin (Obata et al., 1998).
Media and reagents
Luria–Bertani (LB) broth, LB plates, minimal glucose plates and phosphate buffer were used as described previously (Obata et al., 1998; Kobayashi et al., 1998). Nalidixic acid (Nal), streptomycin (Sm), ampicillin (Ap) and chloramphenicol (Cm) were included, if necessary, in media at concentrations of 50, 100, 150 and 30 µg/ml, respectively. Enzymes and reagents used for DNA manipulation and DNA sequencing were purchased from TaKaRa Biomedicals Co. (Kyoto, Japan) and Applied Biosystems Inc. (Foster City, CA). The oligonucleotide 5'-GTACACGAGGCCCTT-3' used as a primer for DNA sequencing was purchased from Sawady Technology Co., Ltd. (Tokyo, Japan).
Irradiation of pTN89 with UV and photoreactivation
Plasmid pTN89 was irradiated with 254 nm UVC, provided by a germicidal lamp (Matsushita Electric Co., Osaka, Japan). The UV fluence rate was 1 J/m2/s. Purified E.coli CPD photolyase (Mizuno et al., 1991) or purified glutathione S-transferase (GST)–Arabidopsis (6–4)photolyase (Nakajima et al., 1998) were used in reaction mixtures of 50 mM Tris–HCl (pH 7.2), 10 mM NaCl, 1 mM EDTA (pH 8.0) and 10 mM dithiothreitol (DTT) to monomerize CPD or (6–4)PP, respectively. Illumination with a daylight fluorescent lamp for photoreactivation was performed for 2 h at room temperature through a 0.2 cm layer of polyvinyl chloride, which absorbs wavelengths of <380 nm (Akasaka and Yamamoto, 1991). When pTN89 was treated with both CPD photolyase and (6–4)photolyase, CPD photoreactivation was performed for 120 min, the plasmid was phenol extracted and (6–4)photoreactivation was performed for another 120 min.
Enzyme-linked immunosorbent assay for CPD and (6–4)PP
CPD or (6–4)PP remaining in the pTN89 plasmid after photoreactivation were quantified using CPD- or (6–4)PP-specific monoclonal antibodies (Mizuno et al., 1991). Direct binding of each monoclonal antibody to CPD or (6–4)PP was measured by an enzyme-linked immunosorbent assay (ELISA) method as described previously (Matsunaga et al., 1990). Aliquots of 100 ng of pTN89 DNA were required for each assay of (6–4)PP; 20 ng of pTN89 DNA was used for each assay of CPD.
Induction of mutations
pTN89 irradiated with UV and photoreactivated or not photoreactivated was introduced by electroporation into exponential-phase cultures of E. coli NKJ3000 in which the SOS response had been induced by 4 J/m2 of UV irradiation and 30 min incubation in LB at 37°C. The cells were grown at 37°C overnight in 5 ml of LB broth supplemented with Ap to allow processing and replication of the plasmids, and the progeny plasmids were extracted from the cells. Progeny plasmids derived from individual transfectants were assayed separately for mutant supF genes, to distinguish mutations that occurred from siblings. KS40/pOF105 cells (Obata et al., 1998) were transformed with the plasmid extracted from NKJ3000 by electroporation, and transformants with mutant supF were plated on minimal glucose plates containing Nal, Sm, Ap and Cm. The total number of transformants was determined by plating a portion of the cells on LB plates containing Ap and Cm after overnight incubation at 37°C. Strain KS40/pOF105 is resistant to Sm and Nal if it contains a mutant supF, whereas cells carrying an active supF do not produce colonies on such plates. The minimal glucose plates were incubated at 37°C for 24 h. Sm- and Nal-resistant colonies were restreaked on LB plates containing 5-bromo-4-chloro-3-indolyl-ß-D-galactoside and isopropyl-ß-D-thiogalactoside, and one of the white colonies was picked for further analysis. All manipulations, except photoreactivation, were carried out under yellow light.
DNA sequencing
Plasmid DNA was extracted from a putative supF mutant transformant and transfected into XL1-BlueMRF' where single-stranded DNA was prepared by infection with M13KO7 helper phage. DNA was sequenced by the dideoxy chain termination method using an automated sequencer (model 373A; Applied Biosystems Inc., Foster City, CA). The polymerization reaction was primed using the appropriate primer.
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Results |
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To identify the mutagenic photoproduct, we treated the UV-irradiated plasmid with photoreactivating enzymes for 2 h in vitro before transfection into SOS-induced E.coli uvrA– phr– cells. To determine whether photoreactivation of UV-irradiated plasmid DNA would increase the transforming activity of the DNA in E.coli NKJ3000, the transforming efficiency of photoreactivated DNA was assayed. Plasmid pTN89 was irradiated at several different UV fluences and then treated with (6–4)photolyase and/or CPD photolyase in vitro. This DNA was used to transform E.coli NKJ3000 and the efficiency of production of ampicillin-resistant colonies was measured. Although photoreactivation of the UV-irradiated pTN89 with (6–4)photolyase alone resulted in transforming activity similar to that without photoreactivation, treatment with CPD photolyase effectively restored the transforming activity of the plasmid DNA (Figure 1
). Photoreactivation with both (6–4)photolyase and CPD photolyase showed higher transforming activity than that after photoreactivation with CPD photolyase alone, consistent with previous observations (Todo et al., 1993). Therefore, it is suggested that the transforming activity of UV-irradiated plasmids in NKJ3000 cells was restored dependent on the removal of (6–4)PP and CPD by (6–4)photolyase and CPD photolyase, respectively.
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, (6–4)photoreactivation; 
, CPD photoreactivation; 
, CPD + (6–4)photoreactivation.To confirm the above conclusion, we assayed the amounts of (6–4)PP and CPD remaining in the pTN89 DNA using monoclonal antibodies against these adducts. As shown in Table I
, (6–4)PP and CPD were almost completely removed after exposure to fluorescent light, depending on the enzymes used. Hence, we concluded that the (6–4)photolyase and the CPD photolyase removed (6–4)PP and CPD on pTN89, respectively, with an efficiency of 
95%.
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To examine the UV-induced mutation, we irradiated the plasmid DNA with 250 J/m2 of UV light followed by photoreactivation in vitro with (6–4)photolyase and CPD photolyase. No photoreactivation, photoreactivation of (6–4)PP, of CPD, and of both (6–4)PP and CPD on UV-irradiated plasmid resulted in supF+ to supF– mutation frequencies of 3.6 x 10–5, 1.5 x 10–5, 9.6 x 10–6 and 8.1 x 10–6, respectively (Table II
). In an unirradiated control we did not obtain any mutations from supF+ to supF–, as expected, because the supF+ to supF– mutation frequency of unirradiated plasmid was low (3.06 x 10–7), as shown in a previous study (Akasaka et al., 1992). Photoreactivation of (6–4)PP alone resulted in a decrease in mutation frequency (Table II). Furthermore, photoreactivation of CPD alone and photoreactivation of both (6–4)PP and CPD resulted in decreases in the mutation frequency, accompanied by increases in the transforming activity of the plasmid (Figure 1
). Thus, (6–4)PP and CPD appeared to contribute to both the transforming activity and mutagenesis of the plasmid in E.coli NKJ3000.
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At least 50 independent UV-induced supF mutant plasmids were recovered and sequenced. Although mutations from unirradiated plasmids were comprised of base substitution, frameshift, IS insertion and deletion, UV-induced mutations were of two types, namely base substitutions and frameshifts, irrespective of photoreactivation (Table II
). Not only single-base substitutions but also tandem base substitutions were observed before and after photoreactivation of both (6–4)PP and CPD. This result was not consistent with previous observation in mammalian cells using the same supF gene as a target where CPD photoreactivation significantly reduced the frequency of tandem double mutant formation (Protic-Sabljic et al., 1986). The frameshift mutations were all single-base deletions at G:C base pairs, which were increased relative to other types of change after photoreactivation of CPD but not (6–4)PP.
More transitions were observed than transversions in UV-induced base substitutions which are different from the spectra of unirradiated control where transversions predominated (Table III). Types of base substitutions in the supF gene after photoreactivation of (6–4)PP were essentially the same as those after no photoreactivation; in both cases, G:CA:T transitions constituted >80% of the total (Table III). As shown in Table III, there was a 5.6-fold decrease in the proportion of G:CA:T transitions, from 84% to 15%, and an increase in A:TG:C transitions from 0% to 83% between non-photoreactivated and CPD photoreactivated DNA mutation spectra. The types of base substitutions after photoreactivation of both (6–4)PP and CPD were different from those after photoreactivation of either (6–4)PP or CPD and those after non-photoreactivation, i.e. both G:CA:T and A:TG:C transitions exist.
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The positions of the supF base changes are shown in Figures 2–4
. Mutations were seen at many sites throughout the supF gene after photoreactivation of (6–4)PP or CPD and without photoreactivation, but the majority of mutations occurred at specific dipyrimidine sites (`hot spots'). Without photoreactivation, UV irradiation induced tandem double mutations at positions 102 and 103, and single-base substitutions at positions 159, 160 and 168 (Figure 2). Dipyrimidines involved at these sites were -TC- or -CC-. After (6–4)PP photoreactivation, tandem double mutations at positions 102 and 103 disappeared but single base substitutions at positions 159, 160 and 168 did not (Figure 3, above the supF sequence). In Figure 3 the changes shown below the supF sequence indicated that photoreactivation of CPD removed the hot spots for base change mutations shown in Figure 2, but created new hot spots at position 135 where 5'-TT-3' can be the dipyrimidine involved. CPD photolyase removes CPD but not (6–4)PP from DNA (Brash et al., 1985), and (6–4) photolyase removes (6–4)PP but not CPD from DNA (Todo et al., 1993). Thus, mutagenic lesions at positions 159, 160 and 168 were -TC- or -CC- CPD and the mutagenic lesion at position 135 was TT-(6–4)PP. Following treatment with both (6–4)photolyase and CPD photolyase, there were three hot spots remaining at positions 135, 159 and 160 (Figure 4). These were the UV-induced hot spots observed after (6–4)PP photoreactivation alone or CPD photoreactivation alone (Figure 3). Thus, base substitutions at positions 135, 159 and 160 after both CPD and (6–4)PP photoreactivation may have been due to (6–4)PP and CPD remaining in the supF gene.
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Tandem double CC
TT mutations at positions 102+103, 103+104, 104+105, 123+124 and 159+160 were removed by CPD photoreactivation. (6–4)PP photoreactivation did not remove tandem double mutations at these sites except for positions 102 and 103. Thus, CC-CPD was the lesion responsible for forming this type of mutation. CCTT mutations at positions 102 and 103 were repaired by both CPD and (6–4)photolyases. Thus, the identities of the mutagenic lesions involved have not yet been determined.
Frameshifts accounted for 3% of the UV-induced mutations; this changed to 16% after CPD photoreactivation (Table II). Frameshifts occurred exclusively at positions 102–105, a stretch of four guanine nucleotides (Figure 3). Thus, CC-(6–4)PP was the lesion responsible. Transversions were observed after photoreactivation of both CPD and (6–4)PP (Table III). All the transversions observed occurred at dipyrimidine sites, and the sites of transversions were essentially the same as those after photoreactivation of CPD alone, (6–4)PP alone and without photoreactivation (Figures 2–4). Thus, the transversions that we observed after photoreactivation of both CPD and (6–4)PP may have been due to unrepaired (6–4)PP and CPD even in the presence of the photolyases.
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Discussion |
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Using a plasmid carrying the E.coli supF gene, CPD photolyase and (6–4)photolyase, we investigated the mutational properties of two UV lesions, CPD and (6–4)PP, in SOS-induced E.coli hosts. Although CPD photolyase has previously been used to demonstrate the mutagenic properties of CPD (Protic-Sabljic et al., 1986
; Hutchinson et al., 1988), (6–4)photolyase was first used to demonstrate the mutagenic role of (6–4)PP in E.coli.
CPD photoreactivation decreased the proportion of G:CA:T transitions from 84% to 15% and increased A:TG:C transitions from 0% to 83% (Table III). Mutations after photoreactivation of both CPD and (6–4)PP comprised 46% A:TG:C transitions, 29% G:CA:T transitions and 26% transversions (Table III). Almost all the G:CA:T transitions before and after photoreactivation occurred mainly at 5'-CC-3' and 5'-TC-3' sites and A:TG:C at 5'-TT-3' sites (Figures 2–4). CPD constituted 90% and (6–4)PP 10% of the photoadducts produced by UV irradiation (Varghese and Wang, 1967; Ikenaga and Jagger, 1971). It is also known that CPD photolyase removes CPD but not (6–4)PP, and (6–4) photolyase removes (6–4)PP but not CPD (Brash et al., 1985; Todo et al., 1993). We therefore came to the following conclusions: (i) CPD at 5'-CC-3' and 5'-TC-3' are mutagenic UV lesions for G:CA:T transitions; and (ii) (6–4)PP at 5'-TT-3' induces A:TG:C transitions. These conclusions were in agreement with previous results (Kunz and Glickman, 1984; Lawrence et al., 1985; Protic-Sabljic et al., 1986; Hutchinson et al., 1988).
When pTN89 DNA was treated with (6–4)photolyase alone, the survival, mutational spectra and the site specificity of one-base substitutions were essentially the same as those without photoreactivation (Figures 1–3; Table III). These results can easily be explained since, as mentioned above, (6–4)PP constitutes ~10% of photoadducts formed by UV irradiation and removing 10% of (6–4)PP cannot have any lethal or mutagenic consequences over the effects of the remaining 90% CPD.
When both (6–4)PP and CPD were removed, we observed differences in the mutational spectra from those after CPD photoreactivation and without photoreactivation; i.e. the presence of both G:CA:T transitions, derived from CC- or TC-CPD, and A:TG:C transitions derived from TT-(6–4)PP (Table III). Thus, we assumed that G:CA:T transitions and A:TG:C transitions seen after treatment with CPD photolyase and (6–4)photolyase were CC- or TC-CPD and TT-(6–4)PP incompletely repaired by the enzymes. Brash et al. (1985) showed previously by chemical assay that some CPD remain after E.coli CPD photolyase treatment.
Tandem double CCTT mutations are known to occur via UV damage of DNA and are thought to be specific indicators of UV exposure (Brash et al., 1991). When UV-irradiated pTN89 is CPD-photoreactivated, tandem double CCTT mutations, at positions 102+103, 103+104, 104+105, 123+124 and 159+160, were completely removed (Figures 2 and 3). (6–4)Photolyase cannot remove CCTT mutations at these sites except at positions 102 and 103 (Figure 3). These results strongly indicated that CC-CPD is responsible for forming this type of mutation. Protic-Sabljic et al. (1986) came to essentially the same conclusions. On the other hand, the identity of the adducts involved in CCTT hot spots at positions 102 and 103 is unclear at present.
Figures 2–4 show the occurrences of other types of tandem double mutations. Although these mutations do not occur frequently, there are some indications that TTCC, TTAC and TTCA mutations are involved and these mutations seem to be removed by (6–4)photolyase but not CPD photolyase (Figure 3). Thus, TT-(6–4)PP may be the lesion responsible. Essentially the same conclusion was reported by Smith et al. (1996) who infected M13 phage containing site-specific (6–4)PP into E.coli and analyzed the mutants obtained.
The proportion of changes due to frameshifts increased from 3% to 16% (Table II) after CPD photoreactivation. The sequencing results shown indicate that all nine frameshifts after CPD photolyase treatment occurred at positions 102–105, a stretch of four guanine (or cytosine) nucleotides (Figure 3). This suggested that frameshifts at positions 102–105 may have been targeted by CC-(6–4)PP. On the basis of CPD photoreactivation studies, Yamamoto (1986) previously demonstrated that the UV-induced reversion of E.coli trpE9777 frameshift allele, which results from the addition of an A:T base pair to a run of five A:T base pairs, was targeted by TT-CPD. It is therefore noteworthy that CC-CPD and TT-(6–4)PP may be involved in base substitutions, and CC-(6–4)PP and TT-CPD formed at stretches of cytosine and thymine nucleotides, respectively, may be involved in frameshifts.
Although a variety of UV photoproducts other than (6–4)PP or CPD have been reported (Gallagher and Duker, 1986; Cadet et al., 1992), the biological significance of such lesions is not well understood. Thus, it is reasonable to assume that the origin of the transversions observed after photoreactivation (Table III) was related to some properties of non-photoreactivable adducts. For example, (6–4)PPs are known to be converted to their Dewar valence isomers by photoreactivating irradiation. Previous reports suggested that Dewar valence isomers have mutagenic effects (LeClerc et al., 1991; Smith et al., 1996). The optimum wavelengths of light for Dewar formation are between 280 and 360 nm (Mitchell and Nairn, 1989; Friedberg et al., 1995). We used polyvinyl chloride during photoreactivation to cut out wavelengths of <380 nm, so we assumed that Dewar valence isomers could not be involved. On the other hand, almost all the transversions observed after photoreactivation of both CPD and (6–4)PP occurred at dipyrimidine sites and the sites of transversions were essentially the same as those after photoreactivation of CPD alone, (6–4)PP alone and without photoreactivation (Figures 2–4). Our results therefore suggested that transversions observed after photoreactivation of both CPD and (6–4)PP were not due to non-photoreactivatable adducts but remaining unphotoreactivated (6–4)PP and CPD even in the presence of the photolyases. Our interpretation was consistent with that of Kamiya et al. (1998) who, using double-stranded plasmids carrying site-specific TT-CPD or TT-(6–4)PP in COS-7 cells, observed the occurrence of T:AG:C and T:AA:T transversions in addition to T:AC:G transitions. However, the possibility cannot be completely ruled out that unknown non-photoreactivatable adducts have mutagenic properties similar to those of (6–4)PPs and CPD.
We found that photoreactivation of the UV-irradiated DNA sometimes caused a change in the site specificity of UV-induced supF mutations. For example, CPD photoreactivation increased the proportion of –G frameshifts at positions 102–105 and A:TG:C transitions at position 135. TT-CPD is formed in DNA at high yields by UV (Rhan and Patrick, 1976) and is more rapidly CPD-photoreactivated than CC-CPD (Myles et al., 1987). Thus, after CPD photoreactivation, there are relative increases in CC-CPD, decreases in TT-CPD and increases in (6–4)PPs that are not repaired. Such a relative change in the constitution of photoproducts in DNA may be effective in formation of –G frameshifts due to persistence of CC-(6–4)PP at positions 102–105 and A:TG:C transitions due to persistence of TT-(6–4)PP at position 135.
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Acknowledgments |
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This research was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (11146201 and 11558067).
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Notes |
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4 To whom correspondence should be addressed. Email: tnkm{at}mail.cc.tohoku.ac.jp
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References |
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Received on February 16, 2000; accepted on September 4, 2000.
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