Long-term persistence of O6-methylguanine in rat brain DNA

Kleihues, Paul; J, Bücheler

doi:10.1038/269625a0

Cited by 68 publications

(27 citation statements)

References 13 publications

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“…Because the neuronal /3 enzyme has recently been shown by physicochemical and catalytic properties to be closely similar to /3 polymerases from other tissues (34), it seems likely that a role in DNA repair might be common to all : polymerases. Although DNA polymerase d does not repair MNU-treated neuronal DNA, this is probably due to the inability of brain tissue to excise alkylated bases (24). DNA repair synthesis by DNA polymerase /3 has been demonstrated after UV-irradiation and after alkylation treatment of mammalian cultured cells in which DNA replication had been inhibited by aphidicolin, a specific inhibitor of DNA polymerase a both in vitro and in vivo (ref.…”

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confidence: 99%

“…The question of whether DNA polymerase y also may function in DNA repair has not been answered; even if the answer were yes, DNA repair synthesis would not have been detected because mitochondria, in general, lack the enzymes necessary for pyrimidine dimer excision (23), and mitochondria from brain may share this tissue's inability to remove alkylated bases from DNA (24).…”

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confidence: 99%

“…However, this polymerase clearly performs no repair synthesis on MNU-treated neuronal DNA. This is probably related to the known inability of brain tissue to excise alkylated bases from DNA (24), a process thought to involve specific N-glycosylases (25). Because MNU is a direct carcinogen that requires no metabolic activation (26), its failure to stimulate DNA synthesis in nuclei cannot be attributed to a lack of reactivity in our experimental system.…”

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confidence: 99%

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Functional roles of DNA polymerases beta and gamma.

Hübscher¹,

Kuenzle²,

Spadari³

1979

Proc. Natl. Acad. Sci. U.S.A.

128

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The physiological functions of DNA polymerases (deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 2.7.7.7) (3 and y were investigated by using neuronal nuclei and synaptosomes isolated from rat brain. UV irradiation of neuronal nuclei from 60-day-old rats resulted in a 7-to 10-fold stimulation of DNA repair synthesis attributable to DNA polymerase # which, at this developmental stage, is virtually the only DNA polymerase present in the nuclei. No repair synthesis could be elicited by treating the nuclei with N-methyl-N-nitrosourea, but this was probably due to the inability of brain tissue to excise alkylated bases from DNA. The role of DNA polymerase y was studied in synaptosomes by using a system mimicking in vivo mitochondrial DNA synthesis. By showing that, under these conditions, DNA The direct assignment of functions to the three mammalian DNA polymerases (deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 2.7.7.7) (a, (, and y) in DNA replication and repair is hampered by the lack of conditional mutants defective in DNA synthesis. To date, one is forced to admit that the evidence presented is at best circumstantial. Despite these reservations, some progress has been made concerning the function of DNA polymerase a. A wealth of information indicates that this enzyme has a major role in DNA replication (reviewed in refs. 1 and 2). Recently, this idea has been further strengthened by the finding that DNA polymerase (v is the major polymerase associated with replicating simian virus 40 chromosomes (3-5). In addition, all aspects of in vitro replicative synthesis by these chromosomes (3) or HeLa cell lysates (6) were found to be resistant to 2',3'-dideoxythymidine 5'-triphosphate (d2TTP), a specific inhibitor of DNA polymerases ( and By but not of DNA polymerase a (3, 6). Conversely, aphidicolin, a selective inhibitor of DNA polymerase at, prevents mitotic division of sea urchin embryos, which requires replicative DNA synthesis, but it has no effect on meiotic division in starfish oocytes, which is not dependent on DNA replication (7). Taken together these observations strongly indicate that DNA polymerase ae is the nuclear replicating enzyme.In contrast, the physiological functions of DNA polymerases (14) and synaptosomea (15) were prepared from the forebrain cortex of 60-day-old and 14-day-old rats (SIV-50 strain), respectively. The preparations were frozen immediately at -70'C until use. Nuclei were counted by using a flow cytophotometer (Phywe, Gottingen, Germany), and protein concentrations were determined by the method of Lowry et al. (16). Repair DNA synthesis in neuronal nuclei and synaptosomes was assayed as described in Table 1.In Vitro System Supporting mtDNA Synthesis in Synaptosomes. Synaptosomes were suspended in 0.32 M sucrose/1 mM KH2PO4, pH 7.5/0.1 mM EDTA and were made permeAbbreviations: BrdUTP, 5-bromo-2'-deoxyuridine 5'-triphosphate; d2TTP, 2',3'-dideoxythymidine 5'-triphosphate; MNU,KN-methyl-N-nitrosourea. t Present address:

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Functional roles of DNA polymerases beta and gamma.

Hübscher¹,

Kuenzle²,

Spadari³

1979

Proc. Natl. Acad. Sci. U.S.A.

128

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“…-35 ' 36 Recently, it was reported that smoking-induced adducts could even be detected in lung DNA of ex-smokers about 10 years after cessation of smoking 37. Downloaded by [University of Illinois at Urbana-Champaign] at 18:17 16 March 2015 …”

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confidence: 99%

Epidemiologic studies of passive smoking and lung cancer: A possible role for Benzo(a)pyrene‐DNA adduct measurements

Leeuwen

Schooten

Kriek

1988

Toxicological & Environmental Chemistry

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“…MNU is rapidly oxidized in a neutral solution and must be applied within minutes of preparation to maintain its carcinogenic effectiveness; it is fully degraded and cleared from the blood within just 15 min (31). MNU is an alkylating agent that produces DNA adducts in tissues within minutes of its administration to rats (32); although some forms of this DNA damage are repaired (33,34), the DNA adducts may prove to be very persistent in specific tissues (35). MNU is also capable of acting as a methyl-group donor for glutathione and cysteine (36) and thus may produce protein adducts, although such findings have not been described.…”

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Protective effects of estrogen in a rat model of age-related cataracts

Bigsby

Cárdenas

Caperell-Grant

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Women have a higher incidence of cataracts, and epidemiologic data suggest that the increased risk may be caused by a lack of estrogen in postmenopausal years. We have examined the effects of estrogen on methylnitrosourea (MNU)-induced cataractogenesis in Sprague-Dawley rats. Animals were ovariectomized, injected with MNU, and treated with estradiol or estrone by a continuous-release, subcutaneous Silastic implant, or they received an empty Silastic implant (no hormone). In the no-hormone group, rats developed opaque lenses approximately 6 months after MNU treatment. By 8 months, 74% (14͞19) of the no-hormone rats had evident opacity in one or both eyes by simple gross inspection; 58% (22͞38) of the eyes in this group were opaque. Estradiol or estrone treatment reduced the incidence of cataractous eyes to 12% or 25%, respectively. Lenses were examined under a dissecting microscope for light transmission. The lenses of the group treated with no hormone had light transmission of 26% ؎ 9.2%, whereas lenses from the estradiol-treated animals had light transmission of 72% ؎ 5.8%. Histological examination revealed that the anterior cortices of the opaque lenses were disrupted and showed the hallmark signs of age-related cataracts; in addition, some eyes that appeared clear by macroscopic examination showed the early histologic signs of cataractogenesis. It was demonstrated with reverse transcription-PCR that lens cells express both ␣ and ␤ types of estrogen receptor, suggesting that the protective effects of the hormones may be a direct, receptor-mediated phenomenon. Thus, the MNU-treated, ovariectomized rat serves as a model for age-related cataractogenesis, and observation of a clear protective effect of estrogens in this system supports the implications of epidemiologic data.More than 75% of people Ն75 years old have some degree of lens opacification (1), and it is estimated that Ͼ50% of blindness is caused by cataracts (2). Age-related cataracts can be classified according to their anatomic location within the lens: cortical, nuclear, posterior, or mixed (3). Women exhibit an increased incidence of cataracts compared with agematched men (4-7), mainly because of a higher rate of cortical cataracts (8, 9). Thus, age-related cataracts present a significant health problem, one that exhibits a sexual dichotomy.Epidemiologic evidence suggests that estrogens may protect against cataracts. Although women are at a higher risk of developing cataracts than are men, this increased risk comes after menopause, when estrogen levels have waned (9, 10). In one study of 544 women, early onset of menopause was associated with a 2.9-fold risk of developing cataracts (11). Moreover, the results of three small epidemiologic studies suggest that postmenopausal estrogen replacement therapy reduces the incidence of cataracts (12)(13)(14). The role of estrogen in modifying the onset of age-related cataractogenesis requires suitable experimental models for further study.Results of animal studies have produced conflicting observation...

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Long-term persistence of O6-methylguanine in rat brain DNA

Cited by 68 publications

References 13 publications

Functional roles of DNA polymerases beta and gamma.

Functional roles of DNA polymerases beta and gamma.

Epidemiologic studies of passive smoking and lung cancer: A possible role for Benzo(a)pyrene‐DNA adduct measurements

Protective effects of estrogen in a rat model of age-related cataracts

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