DNA adducts of chemical carcinogens

Dipple, Anthony

doi:10.1093/carcin/16.3.437

Cited by 257 publications

(192 citation statements)

References 15 publications

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“…The most DNA lesions detected have the character of ALS, and true SSB represented only a minor fraction (Dipple, 1995;Horvathova et al, 1998). These DNA lesions are mainly processed via base excision repair (BER), a mechanism that is responsible for the removal of several classes of damage from DNA employing in early step-specific glycosylases, each recognizing and removing a subset of base damage.…”

Section: Effect Of Saffron and Crocin On Mms-induced Dna Damagementioning

confidence: 99%

Protective Effect of Crocus sativus Stigma Extract and Crocin (trans-crocin 4) on Methyl Methanesulfonate–Induced DNA Damage in Mice Organs

Hosseinzadeh

Abootorabi

Sadeghnia

2008

DNA and Cell Biology

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This study was designed to examine the effect of aqueous extract of Crocus sativus stigmas (CSE) and crocin (trans-crocin 4) on methyl methanesulfonate (MMS)-induced DNA damage in multiple mice organs using comet assay. Adult male NMRI mice in different groups were treated with either physiological saline (10 mL=Kg, intraperitoneal [ip]), CSE (80 mg=Kg, ip), crocin (400 mg=Kg, ip), MMS (120 mg=Kg, ip), and CSE (5, 20, and 80 mg=Kg, ip) 45 min prior to MMS administration or crocin (50, 200, and 400 mg=Kg, ip) 45 min prior to MMS administration. Mice were scarified about 3 h after each different treatment, and the alkaline comet assay was used to evaluate the effect of these compounds on DNA damage in different mice organs. The percent of DNA in the comet tail (% tail DNA) was measured. A significant increase in the % tail DNA was seen in nuclei of different organs of MMS-treated mice. In control groups, no significant difference was found in the % tail DNA between CSE-or crocin-pretreated and saline-pretreated mice. The MMS-induced DNA damage in CSEpretreated mice (80 mg=Kg) was decreased between 2.67-fold (kidney) and 4.48-fold (lung) compared to those of MMS-treated animals alone ( p < 0.001). This suppression of DNA damage by CSE was found to be depended on the dose, which pretreatment with CSE (5 mg=Kg) only reduced DNA damage by 6.97%, 6.57%, 7.27%, and 9.90% in liver, lung, kidney, and spleen, respectively ( p > 0.05 as compared with MMS-treated group). In the same way, crocin also significantly decreased DNA damage by MMS (between 4.69-fold for liver and 6.55-fold for spleen, 400 mg=Kg), in a dose-dependent manner. These data indicate that there is a genoprotective property in CSE and crocin, as revealed by the comet assay, in vivo.

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Section: Effect Of Saffron and Crocin On Mms-induced Dna Damagementioning

confidence: 99%

Protective Effect of Crocus sativus Stigma Extract and Crocin (trans-crocin 4) on Methyl Methanesulfonate–Induced DNA Damage in Mice Organs

Hosseinzadeh

Abootorabi

Sadeghnia

2008

DNA and Cell Biology

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“…In this case, again, the accurate mass measurements of the various fragment ions produced by MS 3 experiments on the LTQ-Orbitrap instrument allowed their unambiguous assignment, and thus the identification of this new adduct as dA-N 6 -IQ. The N 6 nitrogen atom of adenine has already been described as a target for genotoxic agents [32], such as estrogens [27], polycyclic aromatic hydrocarbons [33,34], or aristolochic acid [35]. However, no diagnostic information allowing the determination of the IQ atom involved in the bonding with adenine could be obtained by multi-step MS 3 experiments.…”

Section: Scheme 2 Formation Mechanisms Proposed For Fragment Ions Obmentioning

confidence: 99%

New insights in the formation of deoxynucleoside adducts with the heterocyclic aromatic amines PhIP and IQ by means of ion trap MSⁿ and accurate mass measurement of fragment ions

Jamin

Arquier

Canlet

et al. 2007

J. Am. Soc. Mass Spectrom.

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The formation of adducts by reaction of active metabolites of two heterocyclic aromatic amines (NHOH-PhIP and NHOH-IQ) at nucleophilic sites of deoxynucleosides has been studied by LC-MS n analyses of the obtained reaction mixtures. Sequential MS 3 experiments were carried out on an ion trap mass spectrometer to gain extensive structural information on each adduct detected in the first MS step. Attribution of ions was supported by accurate mass measurements performed on an Orbitrap mass analyzer. Particular attention was given to ions diagnostic of the linking between the heterocyclic aromatic amine (HAA) and the deoxynucleoside. By this way, the structures of five adducts have been characterized in this study, among which two are new compounds: dG-N7-IQ and dA-N 6 -IQ. No depurinating adduct was found in the reactions investigated therein. As expected, the C8 and N 2 p p atoms of dG were found as the most reactive sites of deoxynucleosides, resulting in the formation of two different adducts with IQ and one adduct with PhIP. An unusual non-depurinating dG-N7-IQ adduct has been characterized and a mechanism is proposed for its formation on the basis of the reactivity of arylamines. A dA-N 6 -IQ adduct has been identified for the first time in this work, showing that HAAs can generate DNA adducts with bases other than dG. (J Am Soc

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“…crystal structure ͉ DNA damage ͉ DNA polymerase ͉ protein-DNA complex A lkylating agents are potent environmental carcinogens that are produced by burning tobacco or in grilling foods (1,2) and also may be formed enzymatically in vivo (3,4), for instance, by enzymatic metabolite nitrosation (5). Such agents cause a broad spectrum of DNA lesions.…”

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confidence: 99%

The structural basis for the mutagenicity of O ⁶ -methyl-guanine lesions

Warren

Forsberg

Beese

2006

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

139

178

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Methylating agents are widespread environmental carcinogens that generate a broad spectrum of DNA damage. Methylation at the guanine O 6 position confers the greatest mutagenic and carcinogenic potential. DNA polymerases insert cytosine and thymine with similar efficiency opposite O 6 -methyl-guanine (O6MeG). We combined pre-steady-state kinetic analysis and a series of nine x-ray crystal structures to contrast the reaction pathways of accurate and mutagenic replication of O6MeG in a high-fidelity DNA polymerase from Bacillus stearothermophilus. Polymerases achieve substrate specificity by selecting for nucleotides with shape and hydrogen-bonding patterns that complement a canonical DNA template. Our structures reveal that both thymine and cytosine O6MeG base pairs evade proofreading by mimicking the essential molecular features of canonical substrates. The steric mimicry depends on stabilization of a rare cytosine tautomer in C⅐O6MeG-polymerase complexes. An unusual electrostatic interaction between O-methyl protons and a thymine carbonyl oxygen helps stabilize T⅐O6MeG pairs bound to DNA polymerase. Because DNA methylators constitute an important class of chemotherapeutic agents, the molecular mechanisms of replication of these DNA lesions are important for our understanding of both the genesis and treatment of cancer.crystal structure ͉ DNA damage ͉ DNA polymerase ͉ protein-DNA complex A lkylating agents are potent environmental carcinogens that are produced by burning tobacco or in grilling foods (1, 2) and also may be formed enzymatically in vivo (3, 4), for instance, by enzymatic metabolite nitrosation (5). Such agents cause a broad spectrum of DNA lesions. Although modifications at the O6 position of guanine constitute a minority of the total lesions, they are the most carcinogenic (6-8). The cytotoxic effects of DNA-methylating agents have been exploited in their use as potent anticancer agents. O 6 -methyl-guanine (O6MeG) is mutagenic because polymerases frequently misinsert T opposite O6MeG instead of C, both in vivo (9, 10) and in vitro (11)(12)(13). In this study, we present the crystal structures of complexes of a high-fidelity DNA polymerase with substrates representing several steps of nucleotide insertion opposite O6MeG. Additionally, we have engineered a substrate in which the O6MeG⅐C/T pair lies in DNA outside the binding site of the polymerase, allowing us to compare the conformation of these base pairs in duplex DNA to the conformation of the base pairs constrained in the polymerase active site.The relative preference for incorporation of T and C opposite an O6MeG lesion varies somewhat with polymerase and sequence context (13). High-fidelity polymerases such as exonuclease-deficient E. coli polymerase I (Klenow fragment) (13) or bacteriophage T7 DNA polymerase (11) show an Ϸ7-fold preference for misinsertion of T. By comparison, these polymerases usually show a several thousand-fold preference for insertion of a correct base-pairing partner when copying a normal, undamaged DNA. O6MeG lesions ...

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DNA adducts of chemical carcinogens

Cited by 257 publications

References 15 publications

Protective Effect of Crocus sativus Stigma Extract and Crocin (trans-crocin 4) on Methyl Methanesulfonate–Induced DNA Damage in Mice Organs

Protective Effect of Crocus sativus Stigma Extract and Crocin (trans-crocin 4) on Methyl Methanesulfonate–Induced DNA Damage in Mice Organs

New insights in the formation of deoxynucleoside adducts with the heterocyclic aromatic amines PhIP and IQ by means of ion trap MSⁿ and accurate mass measurement of fragment ions

The structural basis for the mutagenicity of O ⁶ -methyl-guanine lesions

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DNA adducts of chemical carcinogens

Cited by 257 publications

References 15 publications

Protective Effect of Crocus sativus Stigma Extract and Crocin (trans-crocin 4) on Methyl Methanesulfonate–Induced DNA Damage in Mice Organs

Protective Effect of Crocus sativus Stigma Extract and Crocin (trans-crocin 4) on Methyl Methanesulfonate–Induced DNA Damage in Mice Organs

New insights in the formation of deoxynucleoside adducts with the heterocyclic aromatic amines PhIP and IQ by means of ion trap MSn and accurate mass measurement of fragment ions

The structural basis for the mutagenicity of O 6 -methyl-guanine lesions

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New insights in the formation of deoxynucleoside adducts with the heterocyclic aromatic amines PhIP and IQ by means of ion trap MSⁿ and accurate mass measurement of fragment ions

The structural basis for the mutagenicity of O ⁶ -methyl-guanine lesions