Incorporation of Zebularine from its 2′-Deoxyribonucleoside Triphosphate Derivative and Activity as a Template-Coding Nucleobase

Dowd, Casimir L.; Sutch, Brian T.; Haworth, Ian S.; Eritja, Ramón; Márquez, Víctor E.; Yang, Allen S.

doi:10.1080/15257770701795888

Cited by 7 publications

(9 citation statements)

References 37 publications

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“…Third, it is likely that when cellular DNA and RNA polymerases copy a Z-base they do so with relatively high fidelity. It should be noted that Z-base can form two Watson-Crick H-bonds with guanine and this probably the reason why DNA polymerase I Klenow fragment was found to insert a G across it more often than an A [36]. For similar reasons, Z-base may be better tolerated compared to many other base analogs by cellular proteins that interact with nucleic acids.…”

Section: Discussionmentioning

confidence: 99%

Use of Drosophila deoxynucleoside kinase to study mechanism of toxicity and mutagenicity of deoxycytidine analogs in Escherichia coli

et al. 2010

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Most bacteria, including Escherichia coli, lack an enzyme that can phosphorylate deoxycytidine and its analogs. Consequently, most studies of toxicity and mutagenicity of cytosine analogs u se ribonucleosides such as 5-azacytidine (AzaC) and zebularine (Zeb) instead of their deoxynucleoside forms, 5-aza-2'-deoxycytidine (AzadC) and 2'-deoxy-zebularine (dZeb). The former analogs are incorporated into both RNA and DNA creating complex physiological responses in cells. To circumvent this p roblem, we introduced into E. coli the Drosophila deoxynucleoside kinase (DmdNK), which has a relaxed substrate specificity, and tested these cells for sensitivity to AzadC and dZeb. We find that Dm-dNK expression increases substantially sensitivity of cells to these analogs and dZeb is very mutagenic in cells expressing the kinase. Furthermore, toxicity of dZeb in these cells requires DNA mismatch correction system suggesting a mechanism for its toxicity and mutagenicity. The fluorescence p roperties of dZeb were used to quantify the amount of this analog incorporated into cellular DNA of mismatch repair-deficient cells expressing Dm-dNK and the results showed that in a mismatch correction-defective strain a high percentage of DNA bases may be replaced with the analog without long term toxic effects. This study demonstrates that the mechanism by which Zeb and dZeb cause cell death is fundamentally different than the mechanism of toxicity of AzaC and AzadC. It also opens up a new way to study the mechanism of action of deoxycytidine analogs that are used in anticancer chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Use of Drosophila deoxynucleoside kinase to study mechanism of toxicity and mutagenicity of deoxycytidine analogs in Escherichia coli

et al. 2010

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“…The analogue zebularine (derived from pyrimidin-2-one) acts as a cytidine analogue, and in polymerase reactions preferentially directs the incorporation of dGMP. 162 With the pyrimidines the most modified position is C5. 125 I-labelled 5-iodo-dC has been incorporated to the end G-quadruplex structures for use in DNA footprinting to determine the effect of quadruplex-binding ligands and anticancer agents, and can be used effectively with telomeric repeats.…”

Section: Oligonucleotides Containing Modified Sugarsmentioning

confidence: 99%

Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

Loakes

2010

Organophosphorus Chemistry

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“…In order to inhibit DNA methyltransferases this nucleoside must be incorporated to DNA at the GpC methylation sites. Recently it has been shown that 2'-deoxyzebularine triphosphate (dZTP) is incorporated by DNA polymerases opposite to guanine (G) and when Z is at the template it directs dGTP incorporation [5]. In spite of the absence of the amino group, 2'-deoxyzebularine behaved similar to 2'-deoxycytidine pairing with guanine [5][6][7].…”

Section: Synthesis and Hybridization Properties Of Modified Oligodeoxmentioning

confidence: 99%

“…Recently it has been shown that 2'-deoxyzebularine triphosphate (dZTP) is incorporated by DNA polymerases opposite to guanine (G) and when Z is at the template it directs dGTP incorporation [5]. In spite of the absence of the amino group, 2'-deoxyzebularine behaved similar to 2'-deoxycytidine pairing with guanine [5][6][7]. In this report we describe the melting behaviour of DNA duplexes carrying the 1, 2-dihydropyrimidin-2-one (Z) residue opposite to all four natural bases.…”

Section: Synthesis and Hybridization Properties Of Modified Oligodeoxmentioning

confidence: 99%

Synthesis and Hybridization Properties of Modified Oligodeoxynucleotides Carrying Non‐Natural Bases

Aviñó

Pérez-Rentero

Garibotti

et al. 2009

Chemistry & Biodiversity

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The impact of the presence of non-natural bases on the properties of oligodeoxynucleotides has been studied. First, oligodeoxynucleotides carrying 2'-deoxyzebularine were prepared and the stability of duplexes carrying this analogue was determined by DNA melting experiments. Melting temperatures and thermodynamic data showed the preference of 2'-deoxyzebularine for 2'-deoxyguanosine, which behaves as a 2'-deoxycytidine analogue forming a less stable base pair due to the absence of the amino group at position 4. Moreover, the duplex-hairpin equilibrium of a self-complementary oligodeoxynucleotide carrying several natural and non-natural bases including 2'-deoxyzebularine as a central mispair, was studied. Depending of the base present in the middle of the sequence it is possible to affect the stability of the bimolecular duplex modulating the duplex-hairpin equilibrium. Magnesium ions were shown to stabilize preferentially the bimolecular duplex form. The results indicate the importance of the modifications and the role of cations in shifting the structural equilibrium.--

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Incorporation of Zebularine from its 2′-Deoxyribonucleoside Triphosphate Derivative and Activity as a Template-Coding Nucleobase

Cited by 7 publications

References 37 publications

Use of Drosophila deoxynucleoside kinase to study mechanism of toxicity and mutagenicity of deoxycytidine analogs in Escherichia coli

Use of Drosophila deoxynucleoside kinase to study mechanism of toxicity and mutagenicity of deoxycytidine analogs in Escherichia coli

Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

Synthesis and Hybridization Properties of Modified Oligodeoxynucleotides Carrying Non‐Natural Bases

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