Alkylation of DNA and its aftermath

Lawley, P.D.

doi:10.1002/bies.950170615

Cited by 34 publications

(14 citation statements)

References 42 publications

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“…Many studies have dealt with the misincorporation of nucleoside triphosphates opposite O 6 -alkylG residues, which are among the most mutagenic of modifications of DNA by alkylating agents (5,6,54). O 6 -MeG was the first lesion to be studied using the approach of site-specific mutagenesis (in bacterial systems) (8).…”

Section: Discussionmentioning

confidence: 99%

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Choi

Chowdhury

Hong

et al. 2006

Journal of Biological Chemistry

125

207

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Chemical and physical damage to DNA can cause mutations and ultimately cancer, cardiovascular disease, aging, and other diseases (1-4). This damage can result from endogenous agents or exogenous chemicals. Many types of damage are known, and the biological effects can vary considerably. One of the prominent types of damage is alkylation at the O-6 atom of guanine (5, 6). O 6 -AlkylG 4 lesions are some of the more mutagenic lesions formed from DNA-alkylating agents (5, 7). The ability of O 6 -alkylG adducts to cause mutations has been demonstrated directly in site-specific mutagenesis experiments with defined adducts (8 -12). Further support for the view that these are deleterious species derives from the existence of specific DNA repair systems for this type of damage in almost all species, ranging from most bacteria to humans (13,14).Different alkylating agents form O 6 -alkylG adducts, and structure-activity relationships are important for understanding the basic mechanisms of how DNA polymerases function as well as issues such as carcinogenesis. Ϫ and HIV-1 RT (16) and by others with several DNA polymerases, mostly bacterial (7,17,18). Some of the more significant conclusions with pol T7Ϫ and HIV-1 RT were that the bulk of the adduct at the O-6 atom had an inhibitory effect and that an inactive polymerase-oligonucleotide complex is in equilibrium with the functional form (16,19).Studies with pol T7 Ϫ and HIV-1 RT indicated that the effect of size at the N-2 atom is more severe than at the O-6 atom (16, * This work was supported in part by United States Public Health Service Grants R01 CA059887, R01 CA115309 (to L. A. P.), R01 ES010375, and P30 ES000267 (to F. P. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains a MALDI-TOF mass spectrum and capillary gel electrophoresis analysis of the O 6 -PobG 36-mer, an electrophoretic gel showing the lack of extension of an O 6 -PobG:G mispair by pol , and mass spectral analyses used to obtain the results shown in Fig. 7 4 The generic term "alkyl" is used to include both alkyl and aralkyl (Bz) groups for convenience. 5 The abbreviations used are: Bz, benzyl; CID, collision-induced dissociation; dCTP␣S, 2Ј-deoxycytidine 5Ј-O-(1-thiotriphosphate); DTT, dithiothreitol; ESI, electrospray ionization; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MALDI-TOF, matrix-assisted laser desorption ionization/time-of-flight; MS, mass spectrometry; Pob, 4-oxo-4-(3-pyridyl)butyl; PCNA, proliferating cell nuclear antigen; pol, (DNA) polymerase; pol T7 Ϫ , bacteriophage pol T7 exonuclease-deficient; RT, reverse transcriptase; UDG, uracil DNA glycosylase; HIV-1, human immunodeficiency virus, type 1.

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Section: Discussionmentioning

confidence: 99%

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Choi

Chowdhury

Hong

et al. 2006

Journal of Biological Chemistry

125

207

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“…Interstrand cross-links are generally considered to be a more lethal class of DNA lesion given their difficulty to repair and their capacity to impair replication fork progression (Lawley, 1995;Rajski and Williams, 1998;Hurley, 2002;Beljanski et al, 2004). The CpG doublet favored by formaldehyde-activated anthracenediones provides an ideal locale for an interstrand cross-link, given the availability of the two proximal N2 exocyclic amino groups of guanine on opposing DNA strands.…”

Section: Characterization Of Pixantrone-dna Adducts 191mentioning

confidence: 99%

Formaldehyde-Activated Pixantrone Is a Monofunctional DNA Alkylator That Binds Selectively to CpG and CpA Doublets

Evison¹,

Chiu²,

Pezzoni³

et al. 2008

Mol Pharmacol

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The topoisomerase II poison mitoxantrone is important in the clinical management of human malignancies. Pixantrone, a novel aza-anthracenedione developed to improve the therapeutic profile of mitoxantrone, can efficiently alkylate DNA after formaldehyde activation. In vitro transcriptional analysis has now established that formaldehyde-activated pixantrone generates covalent adducts selectively at discrete CpG or CpA dinucleotides, suggesting that the activated complex binds to guanine or cytosine (or both) bases. The stability of pixantrone adduct-induced transcriptional blockages varied considerably, reflecting a mixture of distinct pixantrone adduct types that may include relatively labile monoadducts and more stable interstrand cross-links. 6,9-Bis-[[2-(dimethylamino)ethyl]amino]benzo[g]isoquinoline-5,10-dione (BBR 2378), the dimethyl N-substituted analog of pixantrone, could not form adducts, suggesting that pixantrone alkylates DNA through the primary amino functions located in each side chain of the drug. Pixantrone generated DNA adducts only when guanine was present in substrates and exhibited a lack of adduct formation with inosine-containing polynucleotides, confirming that the N2 amino group of guanine is the site for covalent attachment of the drug. Mass spectrometric analysis of oligonucleotide-drug complexes confirmed that formation of covalent pixantrone-DNA adducts is mediated by a single methylene linkage provided by formaldehyde and that this occurs only with guanine-containing double stranded oligonucleotide substrates. CpG methylation, an epigenetic modification of the mammalian genome, significantly enhanced the generation of pixantrone-DNA adducts within a methylated DNA substrate, indicating that the methylated dinucleotide may be a favored target in a cellular environment.

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“…9,10 Although carcinogens and anticancer drugs are viewed as opposites, the two groups of agents highly overlap ( Figure 1): a. Alkylating agents are classic carcinogens (methylnitrosourea, 7,12-dimethylbenzanthracene, diethylnitrosoamine) and also they are classic anticancer drugs (melphalan, chlorambucil, busulfan, cyclophosphamide, the nitrosoureas, cisplatinum and carboplatin). [11][12][13][14] b. Radiation is both a carcinogenic agent and an effective anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Carcinogenesis, cancer therapy and chemoprevention

Blagosklonny

2005

Cell Death Differ

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Carcinogenesis and cancer therapy are two sides of the same coin, such that the same cytotoxic agent can cause cancer and be used to treat cancer. This review links carcinogenesis, chemoprevention and cancer therapy in one process driven by cytotoxic agents (carcinoagents) that select either for or against cells with oncogenic alterations. By unifying therapy and cancer promotion and by distinguishing nononcogenic and oncogenic mechanisms of resistance, I discuss anticancer-and chemopreventive agent-induced carcinogenesis and tumor progression and, vice versa, carcinogens as anticancer drugs, anticancer drugs as chemopreventive agents and exploiting oncogene-addiction and drug resistance for chemoprevention and cancer therapy.

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Alkylation of DNA and its aftermath

Cited by 34 publications

References 42 publications

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Translesion Synthesis across O6-Alkylguanine DNA Adducts by Recombinant Human DNA Polymerases

Formaldehyde-Activated Pixantrone Is a Monofunctional DNA Alkylator That Binds Selectively to CpG and CpA Doublets

Carcinogenesis, cancer therapy and chemoprevention

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