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Department of Environmental Sciences and Engineering, The University of North Carolina, Chapel Hill, North Carolina 27599
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ABSTRACT |
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Introduction |
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9000 AP sites per cell per day (3)
. These experiments suggest that spontaneous depurination is one of the most frequent promutagenic events in genomic DNA. Furthermore, direct release of bases is also induced by free radical attack of the deoxyribose (4)
. These AP sites have to be repaired efficiently because of their potential cytotoxicity and mutagenicity (5)
. To date, the kinetics of AP site repair have been studied in detail only in in vitro experiments with oligonucleotides and plasmids. The steady-state number of AP sites in genomic DNA has not been characterized because of technical problems related to sensitivity and specificity of existing methods. To better understand the steady state of AP sites at basal levels of base excision repair in vivo, we measured the amount of endogenous AP sites in genomic DNA extracted from various tissues of adult rats and human liver using the ASB assay. In addition, the endogenous AP sites were further characterized by the determination of cleavage sites to the AP sites in these genomic DNAs. |
Materials and Methods |
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7.5 months old. Rats were sacrificed after being anesthetized with metofane. Tissues and organs were quickly harvested and frozen at -80°C until DNA extraction. Eight human liver samples were provided by Dr. C. J. Omiecinski (University of Washington, Seattle, WA; Ref. 6
). DNA was extracted by a procedure slightly modified from the method reported by Nakamura et al. (3)
. Briefly, frozen tissues were thawed and homogenized in PBS with a Tehran homogenizer (Wheaton Instruments, Millville, NJ). After centrifugation at 2,000 x g for 10 min, the nuclear pellets were incubated in lysis buffer (Applied Biosystems) overnight at 4°C with proteinase K (500 mg/ml; Applied Biosystems). DNA was then extracted twice with a mixture of phenol, chloroform, and water and once with Sevag, followed by ethanol precipitation. The extracted DNA was incubated in PBS (pH 7.4) with a mixture of RNase and RNase A. After DNA precipitation with cold ethanol, the DNA pellet was resuspended in sterilized distilled water. The DNA solution was stored at -80°C for the ASB assay. The DNA extraction method used in this study was unlikely to have modified the original number of AP sites in genomic DNA from intact tissues, based on reextraction data of DNA highly exposed to methylmethane sulfonate.
ASB Assay
The AP site assay was performed by a procedure slightly modified from the method reported by Nakamura et al. (3)
. Briefly, 15 µg of DNA in 150 µl of PBS were incubated with 1 mM ARP (Dojindo Laboratories, Kumamoto, Japan) at 37°C for 10 min. After precipitation using cold ethanol, DNA was resuspended in Tris-EDTA buffer. The DNA concentration was measured by a spectrophotometer, and the DNA solution was then prepared at 1.5 µg per 100 µl of Tris-EDTA buffer. Heat-denatured DNA was then immobilized on a NC membrane. The NC membrane was soaked with 5x SSC and then baked in a vacuum oven. The membrane was preincubated with 10 ml of Tris-HCl buffer containing BSA. The NC filter was then incubated in the same solution containing streptavidin-conjugated horseradish peroxidase (BioGenix) at room temperature for 40 min. After the NC membrane was rinsed, the enzymatic activity on the membrane was visualized by the use of enhanced chemiluminescence reagents (Amersham Corp.). The NC filter was then exposed to X-ray film, and the developed film was analyzed using an Ultrascan XL scanning densitometer.
Heat/Acid Treatment of Calf Thymus DNA
Calf thymus DNA was treated with 100 mM MX in 10 mM Tris-HCl buffer-KOH (pH 7.4) at 37°C for 2 h to reduce the original number of AP sites in calf thymus DNA (Sigma). The DNA was purified twice by ethanol precipitation, followed by resuspension in distilled water. The calf thymus DNA pretreated with MX was incubated with heat/acid buffer as described in a previous paper (3)
for various periods of time.
AP Site Cleavage Assay
Regular AP Site Assay.
Fifteen µg of DNA in 135 µl of 10 mM Tris-HCl-KOH buffer (pH 7.5) containing 50 mM NaCl and 5 mM MgCl2 were incubated with 1 mM ARP at 37°C for 10 min, followed by the ASB assay described above.
5' Cleavage Assay.
Fifteen µg of DNA and 145 units of Escherichia coli Exo III (New England Biolabs) in 135 µl of 10 mM Tris-HCl-KOH buffer as described above were incubated at 37°C for 1 min, immediately followed by the ASB assay. The number of 3'-cleaved AP sites was calculated as the original number of AP sites minus the number of AP sites left after treatment with Exo III alone.
3' Cleavage Assay.
Fifteen µg of DNA, 10 mM EDTA, and 100 mM putrescine (Sigma) in 135 µl of 10 mM Tris-HCl-KOH buffer as described above were incubated at 37°C for 30 min, immediately followed by the ASB assay. The number of 5'-cleaved AP sites was calculated as the original number of AP sites minus the number of AP sites left after treatment with putrescine alone.
Detection of Residual AP Sites.
Fifteen µg of DNA and 145 units of Exo III in 110 µ1 of 10 mM Tris-HCl-KOH buffer as described above were incubated at 37°C for 1 min, immediately followed by the addition of a 1/10 volume of 100 mM EDTA. The sample was incubated with 100 mM putrescine in the reaction buffer at 37°C for 30 min, immediately followed by the ASB assay. Residual AP sites showed the number of uncleaved aldehydic lesions after the combination treatment of Exo III and putrescine.
Depurination Assay
Fifteen µg of DNA in 110 µl of PBS (pH 7.4) were incubated at 100°C for 20 min, followed by renaturation at room temperature for 1 h. After incubation with 100 mM putrescine, DNA was reacted with ARP, followed by the ASB assay. The number of heat-labile sites was calculated as the number of AP sites in DNA treated with heat buffer followed by putrescine minus the number of AP sites left after treatment with putrescine alone.
End III-sensitive Assay
Oxidative pyrimidine bases are repaired by End III, leaving AP sites on DNA backbone (5)
. E. coli End III was kindly provided by Dr. Y. W. Kow (Emory University, Atlanta, GA). Fifteen µg of DNA, 1 mM EDTA, 100 mM NaCl, 100 mM putrescine, and E. coli End III (0.1 µg) in 135 µl of 10 mM Tris-HCl-KOH buffer as described above were incubated at 37°C for 30 min, immediately followed by the ASB assay. The number of End III-sensitive sites was calculated as number of AP sites in DNA treated with End III and putrescine minus the number of AP sites left after treatment with putrescine alone.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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but not within tissues. The highest number of AP sites was detected in the brain, with 30 AP sites per 106 nucleotides, followed by the heart and colon. In contrast, rat liver, kidney, and lung consistently showed the lowest number of AP sites (8–9 AP sites per 106 nucleotides). The number of endogenous AP sites in human liver was comparable to that in rat liver. These data indicate that AP sites persist at 50,000–200,000 lesions per mammalian cell under normal physiological conditions. The steady-state number of AP sites in genomic DNA should reflect the balance between the formation and repair of the AP sites. Possible interpretations of the higher number of endogenous AP sites in the brain are as follows: (a) higher rate of depurination and/or endogenous DNA adduct formation, resulting in more AP sites; (b) higher activity of DNA glycosylase, inducing more AP sites; (c) lower activity of type II AP endonuclease, causing accumulation of AP sites; and (d) less efficiency of dRp-ase or ß-elimination, leaving 5'-nicked AP sites.
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. To characterize this AP site cleavage assay, we incubated DNA that had been pretreated with MX to reduce the number of AP sites to 3.8 ± 0.5 AP sites per 106 nucleotides (mean ± SD) with heat and acid buffer. Various periods of heat/acid incubation induced 11, 47, 115, and 320 AP sites per 106 nucleotides. A single treatment of Exo III reduced the number of AP sites by 4–10 AP sites per 106 nucleotides in each DNA sample, regardless of the initial number present (Fig. 3)
. This reduction may be due to the combination of enzymatic incision on the 5' side by Exo III and nonspecific 3' cleavage of AP sites during incubation with Exo III. This nonspecific 3' cleavage precluded precise quantitation of the number of 3'-nicked AP sites in DNA with this assay. In contrast, putrescine treatment showed no reduction in the number of AP sites. After incubation with Exo III followed by putrescine, the number of AP sites was reduced to the original number of AP sites in calf thymus DNA pretreated with MX. The cleavage efficiency of AP sites by the combination of Exo III and putrescine was >99%.
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. Rat and human tissue DNA were incubated with Exo III followed by putrescine to examine whether detected lesions were actual AP sites. After 5' and 3' cleavage of AP sites, 1.5–2.2 residual aldehydic lesions per 106 nucleotides were detected. These data indicate that the ASB assay correctly measures endogenous AP sites. The residual lesions may be due to limitations of enzyme reactions in the AP site cleavage assay as well as to the presence of endogenous aldehydic base lesions such as formyluracil (10)
. In addition, a combined fraction of 3'-cleaved and intact AP sites was detected at 2–3 lesions per 106 nucleotides in different tissues, which is 1/3–1/10 of the total number of endogenous AP sites. To examine the number of 5'-cleaved AP sites, we incubated DNA with putrescine. The reduction of AP sites by putrescine (the original number of AP sites minus the number of AP sites left after putrescine incubation) represented the number of 5'-cleaved AP sites. In contrast to calf thymus DNA pretreated with heat/acid buffer, genomic DNA treated with putrescine had a markedly decreased number of AP sites. These data indicate that approximately two-thirds or more of the endogenous AP sites are already cleaved on the 5' side of AP sites in vivo.
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100-fold lower than the Kcat of AP endonuclease. This study demonstrates a clear persistence of 5'-incised AP sites in rat and human tissues. These data suggest that incision by AP endonuclease and the subsequent release of 5'-dRp residues may not be efficiently linked at a basal level in vivo and that the repair process of 5'-dRp may be one of the rate-limiting steps in base excision repair.
In the previous study (3)
, we demonstrated that spontaneous depurination occurred at 1.5 AP sites per 106 nucleotides per day under physiological conditions. To test whether heat-labile DNA adducts such as N3- and N7-alkyl purines were the source of the higher number of endogenous AP sites in brain, a depurination assay was performed in brain and liver DNA. However, no difference was observed in brain and liver (data not shown). Therefore, the steady state of endogenous AP sites may not be due to labile base lesions. One of the most important and abundant endogenous DNA lesions is oxidative DNA base damage. It has been reported that the steady state of 5-hydroxycytosine in rat brain is 2-fold higher than that in rat liver (19)
. Such oxidative pyrimidine bases are repaired by End III, leaving AP sites on the DNA backbone. To examine whether oxidative stress could be related to the steady-state number of AP sites in DNA, End III-sensitive sites were quantitated using the combination of the ASB assay and E. coli End III. The number of End III-sensitive sites was three times higher in brain (14 lesions per 106 nucleotides) compared to other tissues (4–5 lesions per 106 nucleotides). Recently, the human homologue of the End III (hNTH1) gene has been cloned and characterized (20)
. The mRNA expression of this gene varies between organs in a pattern that corresponds with the number of endogenous AP sites (20)
. Most DNA glycosylases involved in the repair of oxidized bases possess AP lyase activity, which cleaves the 3' side of AP sites. Therefore, endogenous 5' AP sites would not be derived from the cleavages of oxidative bases by such DNA glycosylases. A preliminary experiment showed that hydrogen peroxide with FeSO4 directly induced 5'-cleaved AP sites in calf thymus DNA without any enzymes (data not shown). These studies suggest that oxidative stress might be one of the factors responsible for the steady state of AP sites with 5' cleavage.
We originally expected to find low numbers of endogenous AP sites in genomic DNA because of their toxicity and mutagenicity. However, this study shows that the steady state of AP sites is 1 lesion per 105 nucleotides in genomic DNA. Although AP sites are constantly being repaired, the fraction of AP sites that escapes repair is likely to contribute to mutations, chromosome aberrations, and transcription errors that may be associated with spontaneous age-related diseases such as cancer and degenerative disorders.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Funded in part by National Institute of Environmental Health Sciences Superfund Basic Research Program Grant P42-ES05948. 
2 To whom requests for reprints should be addressed, at Department of Environmental Sciences and Engineering, The University of North Carolina, CB 7400, Chapel Hill, NC 27599-7400.
3 The abbreviations used are: AP, apurinic/apyrimidinic; ARP, aldehyde-reactive probe; ASB, ARP-slot blot; NC, nitrocellulose; MX, methoxyamine; Exo III, exonuclease III; End III, endonuclease III; 5'-dRp, deoxyribose-5-phosphate; dRp-ase, 5'-deoxyribophosphodiesterase; ß-pol, polymerase ß.
Received 2/ 1/99. Accepted 4/15/99.
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P.-H. Lin, J. Nakamura, S. Yamaguchi, P. B. Upton, D. K. La, and J. A. Swenberg Oxidative damage and direct adducts in calf thymus DNA induced by the pentachlorophenol metabolites, tetrachlorohydroquinone and tetrachloro-1,4-benzoquinone Carcinogenesis, April 1, 2001; 22(4): 627 - 634. [Abstract] [Full Text] [PDF]
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P.-H. Lin, J. Nakamura, S. Yamaguchi, D. K. La, P. B. Upton, and J. A. Swenberg Induction of direct adducts, apurinic/apyrimidinic sites and oxidized bases in nuclear DNA of human HeLa S3 tumor cells by tetrachlorohydroquinone Carcinogenesis, April 1, 2001; 22(4): 635 - 639. [Abstract] [Full Text] [PDF]
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M. R. Kelley, L. Cheng, R. Foster, R. Tritt, J. Jiang, J. Broshears, and M. Koch Elevated and Altered Expression of the Multifunctional DNA Base Excision Repair and Redox Enzyme Ape1/ref-1 in Prostate Cancer Clin. Cancer Res., April 1, 2001; 7(4): 824 - 830. [Abstract] [Full Text]
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M. N. Rios-Blanco, T. H. Faller, J. Nakamura, W. Kessler, P. E. Kreuzer, A. Ranasinghe, J. G. Filser, and J. A. Swenberg Quantitation of DNA and hemoglobin adducts and apurinic/apyrimidinic sites in tissues of F344 rats exposed to propylene oxide by inhalation Carcinogenesis, November 1, 2000; 21(11): 2011 - 2018. [Abstract] [Full Text] [PDF]
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M. Sabourin and N. Osheroff Sensitivity of human type II topoisomerases to DNA damage: stimulation of enzyme-mediated DNA cleavage by abasic, oxidized and alkylated lesions Nucleic Acids Res., May 1, 2000; 28(9): 1947 - 1954. [Abstract] [Full Text] [PDF]
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L. J. Marnett Oxyradicals and DNA damage Carcinogenesis, March 1, 2000; 21(3): 361 - 370. [Abstract] [Full Text] [PDF]
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J. Nakamura, D. K. La, and J. A. Swenberg 5'-Nicked Apurinic/Apyrimidinic Sites Are Resistant to beta -Elimination by beta -Polymerase and Are Persistent in Human Cultured Cells after Oxidative Stress J. Biol. Chem., February 25, 2000; 275(8): 5323 - 5328. [Abstract] [Full Text] [PDF]
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J. K. Horton, R. Prasad, E. Hou, and S. H. Wilson Protection against Methylation-induced Cytotoxicity by DNA Polymerase beta -Dependent Long Patch Base Excision Repair J. Biol. Chem., January 21, 2000; 275(3): 2211 - 2218. [Abstract] [Full Text] [PDF]
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H. Atamna, I. Cheung, and B. N. Ames A method for detecting abasic sites in living cells: Age-dependent changes in base excision repair PNAS, January 18, 2000; 97(2): 686 - 691. [Abstract] [Full Text] [PDF]
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 S.H. WILSON, R.W. SOBOL, W.A. BEARD, J.K. HORTON, R. PRASAD, and B.J. VANDE BERG DNA Polymerase {beta} and Mammalian Base Excision Repair Cold Spring Harb Symp Quant Biol, January 1, 2000; 65(0): 143 - 156. [Abstract] [PDF]
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T. A. Ranalli, M. S. DeMott, and R. A. Bambara Mechanism Underlying Replication Protein A Stimulation of DNA Ligase I J. Biol. Chem., January 11, 2002; 277(3): 1719 - 1727. [Abstract] [Full Text] [PDF]
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