Template directed incorporation of nucleotide mixtures using azole- nucleobase analogs

Hoops, Geoffrey C.; Zhang, Peiming; Johnson, W.; Paul, Natasha; Bergstrom, Donald E.; Davisson, V. Jo

doi:10.1093/nar/25.24.4866

Cited by 35 publications

(37 citation statements)

References 30 publications

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“…2). Thus, the mispairing property of oxanine in the DNA template appears broader than the natural universal base, hypoxanthine, which pairs primarily with Cyt and Ade (38).…”

Section: Resultsmentioning

confidence: 99%

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Hitchcock

Dong

Connor

et al. 2004

Journal of Biological Chemistry

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Oxanine (Oxa) is a deaminated base lesion derived from guanine in which the N 1 -nitrogen is substituted by oxygen. This work reports the mutagenicity of oxanine as well as oxanine DNA glycosylase (ODG) activities in mammalian systems. Using human DNA polymerase ␤, deoxyoxanosine triphosphate is only incorporated opposite cytosine (Cyt). When an oxanine base is in a DNA template, Cyt is efficiently incorporated opposite the template oxanine; however, adenine and thymine are also incorporated opposite Oxa with an efficiency ϳ80% of a Cyt/Oxa (C/O) base pair. Guanine is incorporated opposite Oxa with the least efficiency, 16% compared with cytosine. ODG activity was detected in several mammalian cell extracts. Among the known human DNA glycosylases tested, human alkyladenine glycosylase (AAG) shows ODG activity, whereas hOGG1, hNEIL1, or hNEIL2 did not. ODG activity was detected in spleen cell extracts of wild type age-matched mice, but little activity was observed in that of Aag knock-out mice, confirming that the ODG activity is intrinsic to AAG. Human AAG can excise Oxa from all four Oxa-containing double-stranded base pairs, Cyt/Oxa, Thy/Oxa, Ade/Oxa, and Gua/Oxa, with no preference to base pairing. Surprisingly, AAG can remove Oxa from single-stranded Oxacontaining DNA as well. Indeed, AAG can also remove 1,N 6 -ethenoadenine from single-stranded DNA. This study extends the deaminated base glycosylase activities of AAG to oxanine; thus, AAG is a mammalian enzyme that can act on all three purine deamination bases, hypoxanthine, xanthine, and oxanine.

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“…2). Thus, the mispairing property of oxanine in the DNA template appears broader than the natural universal base, hypoxanthine, which pairs primarily with Cyt and Ade (38).…”

Section: Resultsmentioning

confidence: 99%

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Hitchcock

Dong

Connor

et al. 2004

Journal of Biological Chemistry

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“…The present computational investigation of the shape and charge distribution of several nucleoside analogs throws interesting light on the discussion, comment, and related work (16)(17)(18)(19)(20) that has arisen as a consequence of the intriguing results obtained by Kool and co-workers (7)(8)(9)(10)(11). Given that shape and steric effects are presumed to be important with respect to polymerase recognition and selectivity, the question still remains concerning the role if any that electrostatics plays.…”

Section: Discussionmentioning

confidence: 83%

Molecular Moment Similarity Between Several Nucleoside Analogs of Thymidine and Thymidine

1999

Journal of Biomolecular Structure and Dynamics

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Molecular moment descriptors of the shape and charge distributions of twenty five nucleoside structures have been examined. The structures include thymidine as well as the difluorotoluene nucleoside analog which has been found to pair efficiently with adenine by polymerase catalysis. The remaining twenty three structures have been chosen to be as structurally similar to thymidine and to the difluorotoluene nucleoside analog as possible. The moment descriptors which include a description of the relationship of molecular charge to shape show the difluorotoluene nucleoside to be one of the most proximate molecules to thymidine in the space of the molecular moments. The calculations, therefore, suggest that polymerase specificity might be not only a consequence of molecular steric features alone but also of the molecular electrostatic environment and its registration with molecular shape.

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“…The earliest “universal bases” are the azole carboxamide derivatives (Figure 13A) developed by Bergstrom and Davisson [53–55]. These analogs are ambiguous since rotation about the amide bond provides two alternative and mutually exclusive hydrogen-bonding patterns.…”

Section: Who Needs Fidelity? Examples and Applications For The Promismentioning

confidence: 99%

“…These analogs are ambiguous since rotation about the amide bond provides two alternative and mutually exclusive hydrogen-bonding patterns. Secondly, while each non-natural base is similar in shape and size, they differ with respect to chemical composition which provides each with a unique electronic signature [55]. The ability of these analogs to allow degenerate replication was first examined by measuring the ability of Taq DNA polymerase to perform PCR on a DNA template containing each azole derivative [53].…”

Section: Who Needs Fidelity? Examples and Applications For The Promismentioning

confidence: 99%

Non-natural nucleotides as probes for the mechanism and fidelity of DNA polymerases

Lee

Berdis

2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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DNA is a remarkable macromolecule that functions primarily as the carrier of the genetic information of organisms ranging from viruses to bacteria to eukaryotes. The ability of DNA polymerases to efficiently and accurately replicate genetic material represents one of the most fundamental yet complex biological processes found in nature. The central dogma of DNA polymerization is that the efficiency and fidelity of this biological process is dependent upon proper hydrogen-bonding interactions between an incoming nucleotide and its templating partner. However, the foundation of this dogma has been recently challenged by the demonstration that DNA polymerases can effectively and, in some cases, selectively incorporate non-natural nucleotides lacking classic hydrogen-bonding capabilities into DNA. In this review, we describe the results of several laboratories that have employed a variety of non-natural nucleotide analogs to decipher the molecular mechanism of DNA polymerization. The use of various non-natural nucleotides has lead to the development of several different models that can explain how efficient DNA synthesis can occur in the absence of hydrogen-bonding interactions. These models include the influence of steric fit and shape complementarity, hydrophobicity and solvation energies, basestacking capabilities, and negative selection as alternatives to rules invoking simple recognition of hydrogen bonding patterns. Discussions are also provided regarding how the kinetics of primer extension and exonuclease proofreading activities associated with high-fidelity DNA polymerases are influenced by the absence of hydrogen-bonding functional groups exhibited by non-natural nucleotides.DNA polymerases are responsible for chromosome replication, and many play essential roles in DNA repair and recombination. These enzymes add mononucleotides onto the 3′-end of a primer strand using the complementary strand as a template ( Figure 1A). Viewing DNA in this simple two-dimensional projection gives the impression that hydrogen-bonding interactions between the template base and the base of the incoming nucleotides are the most powerful physical forces that stabilize the conformation and structure of nucleic acid. By inference, these hydrogen-bonding interactions are thought to be the primary determinants in base pair recognition during the polymerization reaction. In this case, the mutual recognition of adenine (A)1 by thymine (T) and of guanine (G) by cytosine (C) involves hydrogenbonding interactions between each partner ( Figure 1B). At the atomic level, the non-sp2

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Template directed incorporation of nucleotide mixtures using azole- nucleobase analogs

Cited by 35 publications

References 30 publications

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Molecular Moment Similarity Between Several Nucleoside Analogs of Thymidine and Thymidine

Non-natural nucleotides as probes for the mechanism and fidelity of DNA polymerases

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