The Repair of the Tobacco Specific Nitrosamine Derived Adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by O6-Alkylguanine-DNA Alkyltransferase Variants

Mijal, Renée S.; Thomson, Nicole M.; Fleischer, Nancy L.; Pauly, Gary T.; Moschel, Robert C.; Kanugula, Sreenivas; Fang, Qingming; Pegg, and Anthony E.; Peterson, Lisa A.

doi:10.1021/tx0342417

Cited by 58 publications

(86 citation statements)

References 43 publications

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“…The Ile143 is located in the active site pocket and is very close to the Cys145 acceptor site. However, this protein appears not to differ from wild type in the repair of methylated DNA [19,24,39]. This is not surprising since the position equivalent to Ile143 in hAGT is variable when sequences from a wide range of organisms are compared with the most common alteration being the presence of Val rather than Ile.…”

Section: Discussionmentioning

confidence: 81%

“…However, it is well established that there are striking species differences in the ability of AGTs to repair more bulky adducts [2,49,50]. The I143V/ K178R hAGT was active in the repair of O 6 -n-butylguanine, O 6 -[4-oxo-4-(3-pyridyl)butyl] guanine or BG when these were contained in oligodeoxynucleotides [39]. However, the repair of O 6 -[4-oxo-4-(3-pyridyl)butyl]guanine by this variant was less sensitive to sequence context than wild type or the L84F form [40].…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids for the production of C-terminal His 6 -tagged hAGT [37] and for the production of N-terminal His 6 -tagged hAGT [38], and the mutants L84F, I143V and I143V/K178R were prepared as described previously [39,40]. Plasmids for the production of N-terminal His 6 -tagged W65C and K178R of hAGT were constructed from the template plasmids of pQE30-hAGT [38] with Quick Change Site-directed Mutagenesis Kit used according to the manufacturer's instructions.…”

Section: Construction Of Pqe Plasmids For Expression Of Different Hagmentioning

confidence: 99%

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Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Fang

Loktionova

Moschel

et al. 2008

Biochemical Pharmacology

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The human DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (hAGT) is an important source of resistance to some therapeutic alkylating agents and attempts to circumvent this resistance by the use of hAGT inhibitors have reached clinical trials. Several human polymorphisms in the MGMT gene that encodes hAGT have been described including L84F and the linked double alteration I143V/K178R. We have investigated the inactivation of these variants and the much rarer variant W65C by O 6 -benzylguanine, which is currently in clinical trials, and a number of other second generation hAGT inhibitors that contain folate derivatives (O 4 -benzylfolic acid, the 3' and 5' folate esters of O 6 -benzyl-2'-deoxyguanosine and the folic acid γ ester of O 6 -(p-hydroxymethyl) benzylguanine). The I143V/K178R variant was resistant to all of these compounds. The resistance was due solely to the I143V change. These results suggest that the frequency of the I143V/K178R variant among patients in the clinical trials with hAGT inhibitors and the correlation with response should be considered.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Construction Of Pqe Plasmids For Expression Of Different Hagmentioning

confidence: 99%

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Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Fang

Loktionova

Moschel

et al. 2008

Biochemical Pharmacology

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“…The replacement of Ile by Val has been postulated to affect the acceptance of an alkyl group. However, functional studies of the MGMT 143 V variant protein have found either no difference from the wild-type or a higher activity [32,33]. The 84 F polymorphism has been shown to have similar enzymatic and physicochemical properties to the wild type [34].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

Jiao

Chang

Firozi

et al. 2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O 6 -ethylguanosine (O 6 -EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I 105 V and A 114 V, MGMT L 84 F and I 143 V, XPD D 312 N and K 751 Q, and XRCC3 T 241 M were determined. Demographic and exposure information was collected by in-person interview. Student's t test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O 6 -EtGua levels were 94.6 and 84.8 (3.2-508.1) fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked ≥ 25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P = 0.03). Multiple linear regression models revealed that GSTT1 (β = −2.36, P = 0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (β = −0.08, P = 0.005) and XRCC3 T 241 M (β = 2.22, P = 0.007) in 89 eversmokers. The association between GSTP1 I 105 V, MGMT I 143 V, and XPD D 312 N with the level of adducts was not conclusive. Each polymorphism could explain 2% to 10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T 241 M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

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“…Intriguingly, our recent findings reveal that Bcl2 suppression of DNA mismatch repair occur in a mechanism by directly regulating the heterodimeric hMSH2⅐hMSH6 complex, which leads to enhanced mutagenesis (14). Thus, the oncogenic activity of Bcl2 may result from its inhibitory effects on multiple DNA repair pathways.Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most potent carcinogen contained in cigarette smoke that can induce cellular DNA damage including AP sites of DNA lesions (4,15,16 …”

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confidence: 99%

Bcl2 Inhibits Abasic Site Repair by Down-regulating APE1 Endonuclease Activity

Zhao

Gao

Yang-de

et al. 2008

Journal of Biological Chemistry

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Bcl2 not only prolongs cell survival but also suppresses the repair of abasic (AP) sites of DNA lesions. Apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in the repair of AP sites via the base excision repair pathway. Here we found that Bcl2 down-regulates APE1 endonuclease activity in association with inhibition of AP site repair. Exposure of cells to nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone results in accumulation of Bcl2 in the nucleus and interaction with APE1, which requires all of the BH domains of Bcl2. Deletion of any of the BH domains from Bcl2 abrogates the ability of Bcl2 to interact with APE1 as well as the inhibitory effects of Bcl2 on APE1 activity and AP site repair. Overexpression of Bcl2 in cells reduces formation of the APE1⅐XRCC1 complex, and purified Bcl2 protein directly disrupts the APE1⅐XRCC1 complex with suppression of APE1 endonuclease activity in vitro. Importantly, specific knockdown of endogenous Bcl2 by RNA interference enhances APE1 endonuclease activity with accelerated AP site repair. Thus, Bcl2 inhibition of AP site repair may occur in a novel mechanism by down-regulating APE1 endonuclease activity, which may promote genetic instability and tumorigenesis.Apurinic/apyrimidinic (AP) 2 or abasic sites are the most common form of DNA damage with about 20,000 -50,000 sites produced in each cell/day (1, 2). AP sites can result from spontaneous and chemically initiated hydrolysis through various conditions, including ionizing radiation, UV irradiation, oxidative stress, and exposure to cigarette smoking (1-4). Human apurinic/apyrimidinic endonuclease 1 (APE1) is a major constituent of the base excision repair (BER) pathway of AP sites of DNA lesions (3). Additionally, APE1 is also named as redox effector factor-1 (1) because of its redox abilities on different redox-regulated transcription factors (3, 5). Two activities of this molecule are split into two functionally independent domains of the protein itself: the N terminus is principally devoted to the redox activity, whereas the C terminus exerts enzymatic activity on the repair of AP sites of DNA lesions (3, 5). APE1 specifically binds to abasic sites and cuts the 5Ј phosphodiester bond with its endonuclease activity to produce a DNA primer with 3Ј hydroxyl end, which is a required step in the BER repair pathway (3). Therefore, APE1 is an essential endonuclease and plays a central role in the repair of AP sites of DNA lesions.Bcl2, a major cellular oncogenic protein, plays pivotal roles in enhancing cell survival, retarding G 1 /S cell cycle transition, and attenuating DNA repair (4, 6, 7). Because overexpression of Bcl2 results in lymphomagenesis in transgenic mice, this suggests that Bcl2, in addition to its survival activity, may also potentially have an oncogenic property (8). However, the mechanism(s) by which Bcl2 facilitates oncogenesis is not fully understood. The oncogenic effect of Bcl2 may result from its multiple cellular properties. Bcl2 was originally discovered as a gene product at th...

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The Repair of the Tobacco Specific Nitrosamine Derived Adduct O⁶-[4-Oxo-4-(3-pyridyl)butyl]guanine by O⁶-Alkylguanine-DNA Alkyltransferase Variants

Cited by 58 publications

References 43 publications

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

Bcl2 Inhibits Abasic Site Repair by Down-regulating APE1 Endonuclease Activity

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